Pharmaceutical compounds

SUBSTANCE: invention refers to a compound of formula: , wherein R1 represents C1-4 alkyl; R2 can be specified in C1-4-alkyl, 6-merous aryl, heteroaryl, partially or completely saturated 6-merous heterocyclyl containing 1 heteroatom N or O, C3-10-cycloalkyl, 6-merous aryl-C1-6-alkyl, heteroaryl-C1-6-alkyl or R1 and R2 together with N to which they are attached, can form a 10-merous heteroaryl or a 5-10-merous heterocyclyl group optionally containing 1 additional heteroatom specified in O, N and S, each of which can be optionally substituted, R5 is specified in H, C1-2-alkyl, halogen; R6 is specified in a 6-10-merous aryl, 6-9-merous heteroaryl containing 1-2 heteroatoms specified in O and N; R8 represents H; and to compositions for inhibiting a fatty acid amide hydrolase (FAAH) enzyme.

EFFECT: preparing new pharmaceutical compounds.

20 cl, 2 tbl

Pharmaceutical compounds

The present invention relates to compounds and their use, and in particular, to compounds and their therapeutic use for the treatment or prevention of conditions associated with substrates, such as neurotransmitter anandamide, which are degraded by the enzyme hydrolase amides of fatty acids (FAAH).

The enzyme FAAH breaks down amides of fatty acids, such as anandamide (N-arachidonoylethanolamine), N-oleoylethanolamide, N-palmitoylethanolamide and oleamide. Anandamide, also known as N-arachidonoylethanolamine or AEA, is an endogenous cannabinoid neurotransmitter (a neurotransmitter) found in animal and human organs, mainly in the brain. It was found that anandamide binds vanilloideae receptor. Anandamide is destroyed by the enzyme hydrolase amides of fatty acids (FAAH) to ethanolamine and arachidonic acid. Consequently, the FAAH inhibitors lead to increased levels of anandamide.

Anandamide is a neurotransmitter in the endocannabinoid system and stimulates cannabinoid receptors. Cannabinoid receptors such as CB1 and CB2, receptors are coupled to G protein. CB1 is mainly in the Central nervous system, whereas CB2 is mainly in peripheral tissues. Endocannabinoid system �obleceni in a growing number of physiological functions,
and in the Central and peripheral nervous systems and in peripheral organs. Modulation of the activity of the endocannabinoid system have shown that there are potential therapeutic benefits for a wide number of disparate diseases and pathological conditions. Thus, the endocannabinoid system, and in particular the enzyme FAAH, have become therapeutic targets in the development of potential treatments for many diseases. Endocannabinoid system is associated with regulation of appetite, obesity, metabolic diseases, cachexia, anorexia, pain, inflammation, neurotoxicity, nervous system injury, stroke, multiple sclerosis, spinal cord injury, Parkinson's disease, levodopa-induced dyskinesia, Huntington's disease, syndrome Gilles de La Tourette, tardive dyskinesia, dystonia, amyotrophic lateral sclerosis, Alzheimer's disease, epilepsy, schizophrenia, anxiety, depression, insomnia, nausea, vomiting, alcohol disorders, drug addiction associated with opiates, nicotine, cocaine, alcohol and psychostimulants, hypertension, circulatory shock, impaired reperfusion, atherosclerosis, asthma, glaucoma, retinopathy, cancer, inflammatory diseases of the digestive tract, acute and chronic liver disease,�mi as hepatitis and cirrhosis of the liver,
arthritis and osteoporosis. Endocannabinoid system and the condition with which it is associated, are discussed in detail in the article Pacher et al. (2006) Pharmacol. Rev. 58:389-462.

In order to modulate the level of endogenous FAAH substrates, such as anandamide, which in turn modulates the endocannabinoid system have been developed inhibitors of the enzyme FAAH. They allow, at least partially curing or preventing conditions and diseases associated with the endocannabinoid system.

Since the FAAH substrates associated with other receptors, for example, vanilloideae receptors, and/or is involved in other signaling pathways, inhibitors of FAAH can also allow, at least partially curing or preventing conditions and diseases associated with other pathways or systems, for example, vanilloideae system.

In FR 2915198 and FR 2915199 disclosed compounds that are inhibitors of FAAH.

In US 7,208,504 and FR2915197 also discloses a number of compounds, which differ from the compounds disclosed in FR 2915198 and FR 2915199. These compounds are described as suitable for inhibiting hormone-susceptible lipase (HSL) and monoacylglycerol (MAGL), respectively. However, do not indicate that these compounds are suitable for inhibiting FAAH.

In WO 2009/117444 disclosed compounds that are inhibitors and FAAH and MAGL.

In accordance with the first aspect of Fig�plants proposed connection,
having a formula I or formula II:

where, when the substituent R1 or R2 represents C1-10-alkyl, aryl, heteroaryl, heterocyclyl, C1-6-alkoxy, aryloxy, heteroaromatic, heterocyclic, aryl-C1-6-alkyl, heteroaryl-C1-6-alkyl, aryl-C1-6-alkoxy, heteroaryl-C1-6-alkoxy, heterocyclyl-C1-6-alkoxy, C1-6-alkylamino, C1-6-dialkylamino, C1-6-alkyl, C1-8-cycloalkyl or is a group containing one or more of these components, each of these components may be optional�tive substituted by one or more groups,
R1e is selected from, halogen, C1-10-alkyl, HE, OR1e, OCOR1e, SH, SR1e, SCOR1e, NH2, NO2, NHR1e, NHSO2NH2, NHSO2R1e, NR1eCOR1f, NHC(NH)NH2, NHCOR1e, NR1eR1f, COR1e, CSR1e, CN, COOH, COOR1e, CONH2, CONHOH, CONHR1e, CONHOR1e, C(NOH)NH2, CONR1eR1f, SO2R1e, SO3H, SO2NH2, SO2NR1eR1f where R1e and R1f are independently selected from C1-6of alkyl, substituted C1-6of alkyl, aryl, heteroaryl, S3-8-cycloalkyl and heterocyclyl, or R1e and R1f together with the heteroatom to which they are attached, can form heterocyclyl,

provided that R1 and R2 both denote H or unsubstituted methyl,

or

R1 and R2 together with N to which they are attached, can form a heteroaryl or heterocyclyl group, each of which may be optionally substituted by one or more oxygen atoms or one or more groups selected from aryl, heteroaryl, partially or fully saturated heterocyclyl, S3-8-cycloalkyl, C1-6-alkyl, aryl-C1-6-alkyl, heteroaryl-C1-6-alkyl, heterocyclyl-C1-6-alkyl, C3-8-cycloalkyl-C1-6-alkyl, C1-6-alkoxy, aryloxy, heteroaromatic, heterocyclic, R2a, halogen, HE, OR2a, OCOR2a, SH, SR2a, SCOR2a, NH2, NO2, NHR2a, NHSO2NH2, NHSO2R2a, NR2aCOR2b, NHC(NH)NH2, NHCOR2a, NR2aR2b, COR2a, CSR2a, CN, COOH, COOR2a, CONH2, CONHOH, CONHR2a, CONHOR2a, C(NOH)NH2, CONR2aR2b, SO23H, SO2NH2, SO2NR2aR2b, where R2a and R2b are independently selected from C1-6of alkyl, substituted C1-6of alkyl, aryl, heteroaryl, S3-8-cycloalkyl and heterocyclyl, or R2a and R2b, together with the heteroatom to which they are attached, can form heterocyclyl,

where, when the Deputy of heteroaryl or heterocyclyl formed by using both of R1 and R2 represents aryl, heteroaryl, heterocyclyl, S3-8-cycloalkyl, C1-6-alkyl, aryl-C1-6-alkyl, heteroaryl-C1-6-alkyl, heterocyclyl-C1-6-alkyl, C3-8-cycloalkyl-C1-6-alkyl, C1-6-alkoxy, aryloxy, heteroaromatic, heterocyclic, or a group containing one or more of these components, each of these components can be optionally substituted by one or more groups selected from halogen, hydroxyl, C1-6of alkyl, aryl, heteroaryl, heterocyclyl, S3-8-cycloalkyl, C1-4-alkoxy, aryloxy, heteroaromatic, heterocyclic, S3-8-cycloalkane, aryl-C1-4-alkoxy, heteroaryl-C1-6-alkoxy, heterocyclyl-C1-4-alkoxy, C3-8-cycloalkyl-C1-4-alkoxy, R2c, OR2c, OCOR2c, SH, SR2c, SCOR2c, NH2, NO2, NHR2c, NHSO2NH2, NHSO2R2c, NR2cCOR2d, NHC(NH)NH2, NHCOR2c, NR2cR2d, COR2c, CSR2c, CN, COOH, COOR2c, CONH2, CONHOH, CONHR2c, CONHOR2c, C(NOH)NH2, CONR2cR2d, SO2R2c, - SO3
H, SO2NH2, SO2NR2cR2d, where R2c and R2d are independently selected from C1-6of alkyl, substituted C1-6of alkyl, aryl, heteroaryl, S3-8-cycloalkyl and heterocyclyl, or R2c and R2d, together with the heteroatom to which they are attached, can form heterocyclyl,

where, when Deputy Deputy heteroaryl or heterocyclyl formed by using both of R1 and R2 represents aryl, heteroaryl, heterocyclyl, S3-8-cycloalkyl, C1-6-alkoxy, aryloxy, heteroaromatic, heterocyclic, S3-8-cycloalkane, aryl-C1-4-alkoxy, heteroaryl-C1-6-alkoxy, heterocyclyl-C1-4-alkoxy, C3-8-cycloalkyl-C1-4-alkoxy, or a group containing one or more of these components, each of these components can be optionally substituted by one or more groups selected from C1-4-alkoxy, R2e, halogen, HE, OR2e, OCOR2e, SH, SR2e, SCOR2e, NH2, NO2, NHR2e, NHSO2NH2, NHSO2R2e, NR2eCOR2f, NHC(NH)NH2, NR2eR2f, NHCOR2e, COR2e, CSR2e, CN, COOH, COOR2e, CONH2, CONHOH, CONHR2e, CONHOR2e, C(NOH)NH2, CONR2eR2f, SO2R2e, SO3H, SO2NH2, SO2NR2eR2f where R2e and R2f are independently selected from C1-6of alkyl, substituted C1-6of alkyl, aryl, heteroaryl, S3-8-cycloalkyl and heterocyclyl, or R2e and R2f, together with the heteroatom to which they are attached, can form Goethe�iillil;

where, when ring A is substituted C1-6the alkyl, aryl, heteroaryl, heterocyclyl, C1-6-alkoxy, aryloxy, heteroaromatic, heterocyclic, C1-10-alkyl, C3-8-cycloalkyl, or substituted by a group containing one or more of these components, each of these components can be optionally substituted by one or more groups selected from halogen, Rc, C1-10-alkyl, aryl-C1-6-alkyl, heteroaryl-C1-6-alkyl, heterocyclyl-C1-6-alkyl, HE, ORc, OCORc, SH, SRc, SCORc, NH2, NO2, NHRc, NHSO2NH2NHSO
2Rc, NRcCORd, NHCORc, NHC(NH)NH2, NRcRd, CORc, CSRc, CN, COOH, COORc, CONH2, CONHOH, CONHRc, CONHORc, C(NOH)NH2, CONRcRd, SO2Rc, SO3H, SO2NH2, SO2NRcRd, where Rc and Rd are independently selected from C1-6of alkyl, substituted C1-6of alkyl, aryl, heteroaryl, S3-8-cycloalkyl and heterocyclyl, or Rc and Rd, together with the heteroatom to which they are attached, can form heterocyclyl;

where, when Deputy from R3 mean C1-10-alkyl, aryl, heteroaryl, heterocyclyl, C1-6-alkoxy, aryloxy, heteroaromatic, heterocyclic, C1-6-alkyl, C3-8-cycloalkyl, or means a group containing one or more of these components, each of these components can be optionally substituted by one or more groups selected from halogen, R3e, S1-10-alkyl, HE, OR3e, OCOR3e, SH, SR3e, SCOR3e, NH2, NO2, NHR3e, NHSO2NH2, NHSO2R3e, NR3eCOR3f, NHCOR3e, NHC(NH)NH2, NR3eR3f, COR3e, CSR3e, CN, COOH, COOR3e, CONH2, CONHOH, CONHR3e, CONHOR3e, C(NOH)NH2, CONR3eR3f, SO2R3e, SO3H, SO2NH2, SO2NR3eR3f where R3e and R3f are independently selected from C1-6of alkyl, substituted C1-6-alkyl, �Rila,
heteroaryl, S3-8-cycloalkyl and heterocyclyl, or R3e and R3f, together with the heteroatom to which they are attached, can form heterocyclyl;

where, when R4 mean C1-10-alkyl, aryl, heteroaryl, heterocyclyl, C1-6-alkoxy, aryloxy, heteroaromatic, heterocyclic, C1-6-alkyl, C3-8-cycloalkyl, or means a group containing one or more of these components, each of these components can be optionally substituted by one or more groups selected from halogen, aryl, heteroaryl, heterocyclyl, C1-6-alkoxy, aryloxy, heteroaromatic, heterocyclic, R4c, C1-10-alkyl, HE, OR4c, OCOR4c, SH, SR4c, SCOR4c, NH2, NOz NHR4c,
NHSO2NH2, NHSO2R4c, NR4cCOR4d, NHCOR4c, NHC(NH)NH2, NR4cR4d, COR4c, CSR4c, CN, COOH, COOR4c, CONH2, CONHOH, CONHR4c, CONHOR4c, C(NOH)NH2, CONR4cR4d, SO2R4c, SO3H, SO2NH2, SO2NR4cR4d, where R4c and R4d are independently selected from C1-6of alkyl, substituted C1-6of alkyl, aryl, heteroaryl, S3-8-cycloalkyl and heterocyclyl, or R4c and R4d, together with the heteroatom to which they are attached, can form heterocyclyl,

where, when the Deputy R4 mean C1-10-alkyl, aryl, heteroaryl, heterocyclyl, C1-6-alkoxy, aryloxy, heteroaromatic, heterocyclic, C1-6-alkyl, C3-8-cycloalkyl, or means a group containing one or more of these components, each of these components can be optionally substituted by one or more groups selected from halogen, R4e, C1-10-alkyl, HE, OR4e, OCOR4e, SH, SR4e, SCOR4e, NH2, NO2, NHR4e, NHSO2NH2, NHSO2R4e, NR4eCOR4f, NHCOR4e, NHC(NH)NH2, NR4eR4f, COR4e, CSR4e, CN, COOH, COOR4e, CONH2, CONHOH, CONHR4e, CONHOR4e, C(NOH)NH2, CONR4eR4f, SO2R4e, SO3H, SO2NH2, SO2NR4eR4f, where R4e and R4f are independently selected from C1-6of alkyl, substituted C1-6of alkyl, aryl, heteroaryl, S3-8-cycloalkyl and heterocyclyl, or R4e and R4f, together with the heteroatom to which they are attached, can form heterocyclyl;

R5 together with the ring carbon to which he�oedingen,
can form a carbonyl group, respectively, rearrangement and/or saturation of double bonds in the ring of formula II to which it is attached, or R5 is selected from H, C1-6of alkyl, aryl, heteroaryl, heterocyclyl, S3-8-cycloalkyl, C1-6-alkoxy, aryloxy, heteroaromatic, heterocyclic, R5a, halogen, HE, OR5a, SH, SR5a, OCOR5a, SCOR5a, NH2, NO2, NHR5a, NHSO2NH2, NHSO2R5a, NR5aCOR5b, NHCOR5a, NHC(NH)NH2, NR5aR5b, COR5a, CSR5a, CN, COOH, COOR5a, CONH2, CONHOH, CONHR5a, CONHOR5a, C(NOH)NH2, CONR5aR5b, SO2R5a, SO3H, SO2NH2, SO2NR5aR5b, where R5a and R5b are independently selected from C1-6of alkyl, substituted C1-6of alkyl, aryl, heteroaryl, S3-8-cycloalkyl and heterocyclyl, or R5a and R5b, together with the heteroatom to which they are attached, can form heterocyclyl,

where, when R5 mean C1-6-alkyl, aryl, heteroaryl, heterocyclyl, C1-6-alkoxy, aryloxy, heteroaromatic, heterocyclic, C1-6-alkyl, C3-8-cycloalkyl, or means a group containing one or more of these components, each of these components can be optionally substituted by one or more groups selected from halogen, aryl, heteroaryl, heterocyclyl, C1-6-alkoxy, aryloxy, heteroaromatic, heterocyclic, R5c, C1-6-alkyl, HE, OR5c, OCOR5c, SH, SR5c, SCOR5c, NH2, NO2, NHR5c, NHSO2
NH2, NHSO2R5c, NR5cCOR5d, NHCOR5c, NHC(NH)NH2, NR5cR5d, COR5c, CSR5c, CN, COOH, COOR5c, CONH2, CONHOH, CONHR5c, CONHOR5c, C(NOH)NH2, CONR5cR5d, SO2R5c, SO3H, SO2NH2, SO2NR5cR5d where R5c and R5d are independently selected from C1-6of alkyl, substituted C1-6of alkyl, aryl, heteroaryl, S3-8-cycloalkyl and heterocyclyl, or R5c and R5d, together with the heteroatom to which they are attached, can form heterocyclyl,

where, when Deputy from R5 mean C1-6-alkyl, aryl, heteroaryl, heterocyclyl, C1-6-alkoxy, aryloxy, heteroaromatic, heterocyclic, S3-8-cycloalkyl, or means a group containing one or more of these components, each of these components can be optionally substituted by one or more groups selected from halogen, R5e, C1-6-alkyl, HE, OR5e, OCOR5e, SH, SR5e, SCOR5e, NH2, NO2, NHR5e, NHSO2NH2, NHSO2R5e, NR5eCOR5f, NHCOR5e, NHC(NH)NH2, NR5eR5f, COR5e, CSR5e, CN, COOH, COOR5e, CONH2, CONHOH, CONHR5e, CONHOR5e, C(NOH)NH2, CONR5eR5f, S02R5e, SO3H, SO2NH2, SO2NR5eR5f, where R5e and R5f are independently selected from C1-6of alkyl, substituted C1-6of alkyl, aryl, heteroaryl, S3-8-cycloalkyl and heterocyclyl, or R5e and R5f, together with the heteroatom to which they are attached, can form heterocyclyl;

where, when R6 means heteroaryl or heterocyclyl, each of these components can optionally be substituted by one or more oxygen atoms, and when R6 means C1-6-alkyl, aryl, heteroaryl, heterocyclyl, C1-6-alkoxy, aryloxy, heteroaromatic, heterocyclic, S3-8-cycloalkyl, or means a group containing one or more of these components, each of these components can be optionally substituted by one or more groups selected from halogen, R6c, C1-6-alkyl, C1-6-alkynyl, aryl, heteroaryl, heterocyclyl, C1-6-alkoxy, aryloxy, heteroaromatic, heterocyclic, aryl-C1-6-alkyl, heteroaryl-C1-6
-alkyl, heterocyclyl-C1-6-alkyl, aryl-C1-6-alkoxy, heteroaryl-C1-6-alkoxy, heterocyclyl-C1-6-alkoxy, HE, OR6c, OCOR6c, SH, SR6c, SCOR6c, NH2, NO2, NHR6c, NHC(NH)NH2, NHSO2NH2, NHSO2R6c, NR6cCOR6d, NHCOR6c, NR6cR6d, COR6c, CSR6c, CN, COOH, COOR6c, CONH2, CONHR6c, CONHOR6c, CONHOH, C(NOH)NH2, CONR6cR6d, SO2R6c, SO3H, SO2NH2, SO2NR6cR6d where R6c and R6d are independently selected from C1-6of alkyl, substituted C1-6of alkyl, aryl, heteroaryl, S3-8-cycloalkyl and heterocyclyl, or R6c and R6d, together with the heteroatom to which they are attached, can form heterocyclyl,

where, when Deputy when R6 means heteroaryl or heterocyclyl, each of these components can optionally be substituted by one or more oxygen atoms, and when the Deputy when R6 means C1-6-alkyl, C1-6-alkynyl, aryl, heteroaryl, heterocyclyl, C1-6-alkoxy, aryloxy, heteroaromatic, heterocyclic, aryl-C1-6-alkyl, heteroaryl-C1-6-alkyl, heterocyclyl-C1-6-alkyl, aryl-C1-6-alkoxy, heteroaryl-C1-6-alkoxy, heterocyclyl-C1-6-alkoxy, C3-8-cycloalkyl, or means a group containing one or more of these components, each of these components can be optionally substituted by one or more groups selected from halogen, R6e, C1-6-alkyl�,
With1-4-alkoxy, HE, OR6e, OCOR6e, SH, SR6e, SCOR6e, NH2, NO2, NHR6e, NHC(NH)NH2, NHSO2NH2, NHSO2R6e, NR6eCOR6f, NHCOR6e, NR6eR6f, COR6e, CSR6e, CN, COOH, COOR6e, CONH2, CONHOH, CONHR6e, CONHOR6e, C(NOH)NH2, CONR6eR6f, SO2R6e, SO3H, SO2NH2, SO2NR6eR6f where R6e and R6f are independently selected from C1-6of alkyl, substituted C1-6of alkyl, aryl, heteroaryl, S3-8-cycloalkyl and heterocyclyl, or R6e and R6f, together with the heteroatom to which they are attached, can form heterocyclyl;

where, when R7 means heteroaryl or heterocyclyl, each of these components can optionally be substituted by one or more oxygen atoms, and when R7 mean C1-6-alkyl, aryl, heteroaryl, g�eroticly,
C1-6-alkoxy, aryloxy, heteroaromatic, heterocyclic, S3-8-cycloalkyl, or means a group containing one or more of these components, each of these components can be optionally substituted by one or more groups selected from halogen, R7c, C1-6-alkyl, C1-6-alkynyl, aryl, heteroaryl, heterocyclyl, C1-6-alkoxy, aryloxy, heteroaromatic, heterocyclic, aryl-C1-6-alkyl, heteroaryl-C1-6-alkyl, heterocyclyl-C1-6-alkyl, aryl-C1-6-alkoxy, heteroaryl-C1-6-alkoxy, heterocyclyl-C1-6-alkoxy, HE, O7c, OCOR7C, SH, SR7c, SCOR7c, NH2, NO2, NHR7c, NHC(NH)NH2, NHSO2NH2, NHSO2R7c, NR7cCOR7d, NHCOR7c, NR7cR7d, COR7c, CSR7c, CN, COOH, COOR7c, CONH2, CONHR7c, CONHOR7c, CONHOH, C(NOH)NH2, CONR7cR7d, SO2R7c, SO3H, SO2NH2, SO2NR7cR7d where R7c and R7d are independently selected from C1-6of alkyl, substituted C1-6of alkyl, aryl, heteroaryl, S3-8-cycloalkyl and heterocyclyl, or R7c and R7d, together with the heteroatom to which they are attached, can form heterocyclyl,

where, when Deputy R7 means heteroaryl or heterocyclyl, each of these components can optionally be substituted by one or more oxygen atoms, and when the Deputy when R7 mean C1-6-alkyl, C1-6-alkynyl, aryl, heteroaryl, heterocyclyl, C1-
-alkoxy, aryloxy, heteroaromatic, heterocyclic, aryl-C1-6-alkyl, heteroaryl-C1-6-alkyl, heterocyclyl-C1-6-alkyl, aryl-C1-6-alkoxy, heteroaryl-C1-6-alkoxy, heterocyclyl-C1-6-alkoxy, C3-8-cycloalkyl, or means a group containing one or more of these components, each of these components can be optionally substituted by one or more groups selected from halogen, aryl, heteroaryl, heterocyclyl, aryl-C1-6-alkyl, heteroaryl-C1-6-alkyl, heterocyclyl-C1-6-alkyl, C1-4-alkoxy, R7e, C1-6-alkyl, HE, OR7e, OCOR7e, SH, SR7e, SCOR7e, NH2, NO2, NHR7e, NHSO2NH2, NHSO2R7e, NHC(NH)NH2, NR7eCOR7f, NHCOR7e, NR7eR7f, COR7e, CSR7e, CN, COOH, COOR7e, CONH2, CONHOH, CONHR7e, CONHOR7e, C(NOH)NH2, CONR7eR7f, SO2R7e, SO3H, SO2NH2, SO2NR7eR7f where R7e and R7f are independently selected from C1-6of alkyl, substituted C1-6of alkyl, aryl, heteroaryl, S3-8-cycloalkyl and heterocyclyl, or R7e and R7f, together with the heteroatom to which they are attached, can form heterocyclyl;

where, when the Deputy R8 means C1-6-alkyl, aryl, heteroaryl, heterocyclyl, C1-6-alkoxy, aryloxy, heteroaromatic, heterocyclic, aryl-C1-6-alkyl, heteroaryl-C1-6-alkyl, heterocyclyl-C1-6-alkyl, aryl-C1-6-alkoxy, heteroaryl-C1-6-alkoxy, heterocyclyl-C1-6-alkoxy, C3-8-cycloalkyl, or means a group containing one or more of these components, each of these components can be optionally substituted by one or more groups selected from halogen, R8e, C1-6-alkyl, HE, OR8e, OCOR8e, SH, SR8e, SCOR8e, NH2, NO2, NHR8e, NHSO2NH2, NHSO2R8e, NR8eCOR8f, NHCOR8e, NHC(NH)NH2, NR8eR8f, COR8e, CSR8e, CN, COOH, COOR8e, CONH2, CONHOH, CONHR8e, CONHOR8e, C(NOH)NH2, CONR8eR8f, SO2R8e, SO3H, SO2NH2, SO2NR8eR8f where R8e and R8f are independently selected from C1-6of alkyl, substituted C1-6of alkyl, aryl, heteroaryl, S3-8-cycloalkyl and heterocyclyl, or R8e and R8f, together with the heteroatom to which they are attached, can form heterocyclyl;

where, at most, two atoms or groups denoted X, Y and Z can represent N;

where W stands for N, CONR1R2 group can be prisoedinennymi W with the corresponding rearrangement of double bonds in formula I;

or their pharmaceutically acceptable salts or esters;

provided that when R1 and R2 together form piperidinyl in the compounds of formula I, piperidinyl not substituted bromide, dimetilan, ethyl, isopropyl, tert-butyl, methoxycarbonyl, trifluoromethyl sulfide, chlorine, bromine or benzyl,

provided that R1 and R2 together in compounds having formula I does not form a 6,7-dimethoxy-3,4-dihydro-1H-isoquinoline-2-yl, 6-methoxy-3,4-dihydro-1H-isoquinoline-2-yl, 7-methoxy-3,4-dihydro-1H-isoquinoline-2-yl, 7-amino-3,4-dihydro-1H-isoquinoline-2-yl, 7-nitro-3,4-dihydro-1H-isoquinoline-2-yl, 3,4-dihydro-1H-isoquinoline-2-yl, 3,4-dihydro-1H-isoquinoline-1-yl, 3,4-dihydro-2H-quinolin-1-yl, pyrrolidin-1-yl, 3,6-dihydro-2H-pyridin-1-yl, 8-Aza-Spiro[4.5]Dec-8-yl, 1,3-dihydroindol-2-yl, octahydrocyclopenta-2-yl, 1,2,6-triaza-Spiro[2.5]Oct-1-EN-6-yl or azepin-1-yl,

provided that when R1 or R2 signifies unsubstituted methyl, the other of R1 or R2 does not mean 4-chlorobutyl, 4-azidomethyl, or 4-izotiotsianovoy,

provided that ring A in compounds having formula I does not form a pyridine, pyrimidine, substituted pyridine or substituted pyrimidine, when R1 and R2 together with N to which they are attached, form piperidinyl, piperazinyl, substituted piperidinyl or substituted piperazinyl, and

provided that the compound is not (4-phenyl-1H-imidazol-1-yl)(4-(quinolin-2-ylmethyl)piperazin-yl)methanon.

It was found that the compounds of the invention modulate the activity of the enzyme hydrolase amides of fatty acids (FAAH). In particular, the compounds possess inhibitory properties against this enzyme and exert inhibition of FAAH in vitro at concentrations of 10 μm or less. In addition, many of these compounds show strong inhibition of FAAH in vitro at a concentration of 100 nm or less and also exert inhibition in vivo in tissues of the Central nervous system and peripheral tissues. It was also found that the compounds according to the invention is relatively specific for FAAH, so that they exhibit relatively low inhibition of other serine hydrolases, for example, monoacylglycerol hydrolase. They are also relatively metabolically stable and exhibit a relatively high affinity for FAAH. This means that you can expect that they will show relatively long-term inhibitory effect on FAAH.

In addition, it was found that some compounds of the invention are selective in such a way that they inhibit FAAH to a greater extent in the tissues of the Central nervous system compared with peripheral tissues. It has been found that other compounds are selective in such a way that they inhibit FAAH to a greater extent in peripheral tissues compared with tissues of the Central nervous �fluid systems.

It was found that some compounds of the invention are extremely suitable for introduction into the lungs of the subject. It was found that the compounds can effectively inhibit FAAH in the lungs until you pass into the bloodstream of the subject. Thus, they have localized inhibitory effect on FAAH more than a systemic effect.

As used herein, the term "Cx-y-alkyl" refers to linear or branched saturated hydrocarbon group containing from x to y carbon atoms. For example, C1-6-alkyl refers to linear or branched saturated hydrocarbon group containing from 1 to 6 carbon atoms. Examples of C1-6-alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl and hexyl. Preferably, the hydrocarbon groups are linear. Group C1-10alkyl preferably represents C1-6-alkyl. The term "Cx-y-alkyl" is also used in the designation of linear or branched saturated hydrocarbon group containing from x to y carbon atoms in which the terminal methyl group is further substituted, i.e. in order to introduce Cx-y-alkylenes group.

As used herein, the term "Cx-y-alkynyl" refers to linear or branched hydrocarbon group�e,
containing from x to y carbon atoms and at least one carbon-carbon triple bond. For example, C1-6-alkynyl refers to linear or branched hydrocarbon group containing from 1 to 6 carbon atoms. Examples of C1-6-etkinlik groups include ethinyl, methylbutanal (for example, 3-methyl-1-butinyl), 1,3-butadiene and 1,3,5-hexatriene.

As used herein, the term "aryl" refers to C6-12monocyclic or bicyclic hydrocarbon rings, where at least one ring is aromatic. Examples of such groups include phenyl, naphthalenyl and tetrahydronaphthalene.

Used here, the term "heteroaryl substituted by one or more oxygen atoms" refers to a heteroaryl ring which has one or more oxygen atoms associated with the ring. This does not mean that the heteroaryl ring contains one or more oxygen atoms as ring atoms, although in some embodiments there may be such cases. Preferably, one or more oxygen atoms linked to the nitrogen heteroatom in the heteroaryl ring. Heteroaryl substituted by one or more oxygen atoms, may contain N-oxide. An example of heteroaryl substituted by one or more oxygen atoms is 1-oxide pyridyl in which the nitrogen of pyridyl is oxidized.

The term "heterocyclyl substituted by one or more oxygen atoms" refers to a heterocyclic ring which has one or more oxygen atoms associated with the ring. This does not mean that the heterocyclic ring contains one or more oxygen atoms as ring atoms, although in some embodiments there may be such cases. Preferably, one or more oxygen atoms linked to a heteroatom, such as nitrogen or sulfur, in the heterocyclic ring. Example heterocyclyl, substituted �ne or more oxygen atoms,
is 1,1-dioxido-1,3-thiazolidine.

The terms "bicyclic ring" and "condensed" in the context of the bicyclic ring refers to the two rings which are linked together through a bond between two atoms (e.g., naphthalene), through a sequence of atoms with the formation of the bridge (e.g., Hinkley) or together with a single atom with the formation of Spiro-compounds (e.g., 1,4-dioxa-8-Aza-Spiro[4.5]decane and N,3,3-dimethyl-1,5-dioxaspiro[5.5]Formica-9-yl).

As used herein, the term "Cx-y-cycloalkyl" refers to a saturated hydrocarbon rings containing from x to y carbon atoms that may be mono, bi or tricyclic. For example, With3-10-cycloalkyl refers to a saturated mono -, bi-or tricyclic hydrocarbon ring containing from 3 to 10 carbon atoms. Examples of C3-10-cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and adamantyl.

As used herein, the term "aryl-(Cx-y-alkyl" refers to an aryl group as defined above, associated with Cx-y-alkyl defined above. For example, aryl-C1-6-alkyl refers to an aryl group associated with linear or branched saturated hydrocarbon group containing from 1 to 6 carbon atoms. Examples of aryl-C1-6-alkyl groups include sec�nil,
phenethyl, phenylpropyl, phenylbutyl, phenylpentyl and phenylhexa.

As used herein, the terms "heteroaryl-Cx-y-alkyl", "heterocyclyl-Cx-y-alkyl" and "Cx-y-cycloalkyl-Cx-y-alkyl" refers to heteroaryl, heterocyclyl or Cx-y-cycloalkyl group, as defined above, associated with Cx-y-alkyl defined above.

As used herein, the term "Cx-y-alkoxy" refers to-O-Cx-y-alkyl group, where Cx-y-alkyl is as defined above. Examples of such groups include methoxy, ethoxy, propoxy, butoxy, pentox and hexose.

As used herein, the term "aryloxy" refers to-O-aryl group. Examples of such groups include phenoxy. Used herein, the terms "heteroaromatic and heterocyclic" refers to the groups-O-heteroaryl and-O-heterocyclyl, respectively.

As used herein, the term "halogen" refers to fluorine, chlorine, bromine and iodine, unless otherwise specified.

As used herein, the term "Cx-y-alkylamino" refers to a secondary amino group (-NH(R)), in which the group R is selected from linear or branched saturated hydrocarbon group containing from x to y carbon atoms. Examples of Cx-y-alkylamino groups include methylamino, ethylamino and propylamino.

As used herein, the term "Cx-y-dialkylamino" refers � tertiary amino group (-NR(R*)),
in which groups R and R* each independently selected from linear or branched saturated hydrocarbon group containing from x to y carbon atoms. Examples of Cx-y-dialkylamino groups include dimethylamino, methylethylamine and diethylamino.

As used herein, the term "substituted C1-6-alkyl", in relation to the identity of the various groups identified as R (for example, in the phrase "where R8e and R8f are independently selected from C1-6of alkyl, substituted C1-6of alkyl, aryl, heteroaryl, S3-8-cycloalkyl and heterocyclyl"), means that the group R (for example, R1a, R2c, R4d, R5e, etc.) may be substituted by one or more groups selected from R', halogen, HE, OR', SH, SR', OCOR', SCOR', NH2, NO2, NHR', NHSO2NH2, NHSO2R', NR'COR", NHC(NH)NH2, NHCOR', NR'R", COR', CSR', CN, COOH, COOR', CONH2, CONHOH, CONHR', CONR'R", CONHOR', C(NOH)NH2, SO2R', SO3H, SO2NH2, SO2NR'R", where R' and R" are independently selected from C1-6of alkyl, aryl, heteroaryl, S3-8-cycloalkyl and heterocyclyl, or R' and R", together with the heteroatom to which they are attached, can form heterocyclyl.

"Pharmaceutically acceptable salts" of the compounds of the present invention include salts with inorganic bases, salts with organic bases, salts with inorganic acids, salts with organic acids and salts with basic Il� acidic amino acids.
Salts with acids, in particular, can be performed in various embodiments. Examples of salts include the following salts: hydrochloride, acetate, Triforce, methanesulfonate, 2-hydroxypropan-1,2,3-tricarboxylate, (2R,3R)-2,3-dihydrochalcone, phosphate and oxalate. The compound of the present invention can be either in solvated (e.g., hydrate), or not solvated (e.g. hydrate) form. In the case of a solvated form of additional solvents can be alcohols such as propan-2-ol.

"Pharmaceutically acceptable esters of compounds of the invention are derivatives in which one or more carboxyl groups (i.e.,- C(O)OH) of these compounds are modified by reaction with an alcohol component U-OH with the formation of the groups-C(O)OU where U can mean C1-18-alkyl (e.g., C1-6-alkyl), aryl, heteroaryl, S3-8-cycloalkyl or a combination thereof.

The main methods of obtaining salts and esters are well known to the person skilled in the art. Pharmaceutically acceptable salts and esters will depend on various factors, including the characteristics of the process of obtaining and behavior in vivo, and the specialist can easily identify such factors that are related to the present disclosure.

If the compounds of the invention exist in different enantiomeric or diastereoisomeric forms (vklyuchaemykh isomerism about the double bond),
these compounds can be obtained as mixtures of isomers or racemates, although the invention applies to all such enantiomers or isomers when they are in optically pure form or as a mixture with other isomers. Individual enantiomers or isomers can be obtained by known in the art methods such as the structures of optical isomers of the products or intermediate products (e.g., chiral chromatographic separation (e.g. chiral HPLC)), or a suitable enantiomeric synthesis. Similarly, if a compound of the invention may exist in alternative tautomeric forms (for example, keto/enol, amide/imide acid), the invention relates to allocated to the individual tautomers and mixtures of tautomers in all their relationships.

In compounds of formula II, zero, one, or two atoms or groups denoted X, Y and Z can mean N.

In a particular embodiment of the invention, the compounds of the invention have a formula selected from Formula I or Formula II:

R1 and R2 together with N to which they are attached, can form a heteroaryl or heterocyclyl group, each of which may be optionally substituted by one or more groups selected from hydroxyl, aryl, heteroaryl, heterocyclyl, S3-8-cycloalkyl, C1-6-alkyl, aryl-C1-6-alkyl, heteroaryl-C1-6-alkyl, heterocyclyl-C1-6-alkyl, C3-8-cycloalkyl-C1-6-alkyl, C1-6-alkoxy, aryloxy, heteroaromatic and heterocyclic, each of which may be optionally substituted by a group selected from halogen, hydroxyl, C1-4of alkyl, aryl, heteroaryl, heterocyclyl, S1-4-alkoxy, aryloxy, heteroaromatic, aryl-C1-4-alkoxy and heteroaryl-C1-4-alkoxy, each of which, except halogen and hydroxyl, optionally can be substituted With
-alkoxy;

ring A is selected from aryl, heteroaryl and heterocyclyl components, each of which may be optionally substituted by one or more groups selected from halogen, hydroxyl, aryl, heteroaryl, heterocyclyl, C1-6-alkoxy, aryloxy, heteroaromatic and heterocyclic, each of which, except halogen and hydroxyl, optionally may be substituted by halogen, cyano, amide and carboxylic acid;

V may mean N, CH or C-R3, where R3 means halogen, aryl, heteroaryl, heterocyclyl or C3-8-cycloalkyl, each of which, except halogen, optionally be substituted by halogen;

W may denote N, CH or C-R4, where R4 means With1-10-alkyl, aryl, heteroaryl, heterocyclyl or C3-8-cycloalkyl, each of which can optionally be substituted by halogen;

R5 is selected from H, C1-6of alkyl, aryl, heteroaryl, heterocyclyl or C3-8-cycloalkyl, each of which, except H, can optionally be substituted by halogen;

X can mean N, CH or C-R6, where R6 is selected from C1-6of alkyl, aryl, heteroaryl and heterocyclyl, each of which, except H, can optionally be substituted by one or more groups selected from halogen, hydroxyl, amine, amide, cyano, aryl, heteroaryl, heterocyclyl, S1-6-al�hydroxy,
aryloxy, heteroaromatic, heterocyclic, aryl-C1-6-alkyl, heteroaryl-C1-6-alkyl, heterocyclyl-C1-6-alkyl, aryl-C1-6-alkoxy, heteroaryl-C1-6-alkoxy and heterocyclyl-C1-6-alkoxy;

Y can mean N, CH or C-R7, where R7 is selected from C1-6of alkyl, aryl, heteroaryl and heterocyclyl, each of which, except H, can optionally be substituted by one or more groups selected from halogen, aryl, heteroaryl, heterocyclyl, S1-6-alkoxy, aryloxy, heteroaromatic, heterocyclic, aryl-C1-6-alkyl, heteroaryl-C1-6-alkyl, heterocyclyl-C1-6-alkyl, aryl-C1-6-alkoxy, heteroaryl-C1-6-alkoxy and heterocyclyl-C1-6-alkoxy, each of which can optionally be substituted C1-4the alkyl, cyano, amine, amide, halogen, aryl, heteroaryl, heterocyclyl, aryl-C1-6-alkyl, heteroaryl-C1-6the alkyl and heterocyclyl-C1-6-alkyl;

Z may denote N, CH or C-R8, where R8 is selected from C1-10of alkyl, aryl, heteroaryl, heterocyclyl or C3-8-cycloalkyl, each of which can optionally be substituted by halogen;

or their pharmaceutically acceptable salts or esters;

provided that when R1 and R2 together form piperidinyl in the compounds of formula I, piperidinyl not substituted bromide, Dimethylol ethyl,
the isopropyl, tert-butyl, trifluoromethyl sulfide, chlorine, bromine or benzyl.

According to another embodiment of the invention provides a compound of formula I or formula II:

where, when R1 or R2 represents C1-20-alkyl, alkoxy, aryl, heteroaryl, heterocyclyl, S3-10-cycloalkyl, aryl-C1-6-alkyl, heteroaryl-C1-6-alkyl, heterocyclyl-C1-6-alkyl, C3-10-cycloalkyl-C1-6-alkyl, C1-6-alkyl, C3-8-cycloalkyl or is a group containing one or more of these components, each of these components can be optionally substituted by one or more groups selected� of R1c,
of halogen, C1-6of alkyl, aryl, heteroaryl, heterocyclyl, S1-6-alkoxy, aryloxy, heteroaromatic, heterocyclic, aryl-C1-6-alkyl, heteroaryl-C1-6-alkyl, heterocyclyl-C1-6-alkyl, aryl-C1-6-alkoxy, heteroaryl-C1-6-alkoxy, heterocyclyl-C1-6-alkoxy, C1-6-alkylamine, C1-6-dialkylamino, C1-10-alkyl, HE, OR1c, OCOR1c, SH, SR1c, SCOR1c, NH2, NHR1c, NR1cR1d, COR1c, CSR1c, CN, COOH, COOR1c, CONH2, SO2R1c, SO3H, SO2NH2, CONR1cR1d, SO2NR1cR1d, where R1c and R1d are independently selected from C1-6of alkyl, substituted C1-6-alkyl, C3-8-cycloalkyl and heterocyclyl, and R1c and R1d together with the adjacent heteroatom, can form heterocyclyl,

where, when the Deputy of R1 or R2 means C1-10-alkyl, aryl, heteroaryl, heterocyclyl, S1-6-alkoxy, aryloxy, heteroaromatic, heterocyclic, aryl-C1-6-alkyl, heteroaryl-C1-6-alkyl, heterocyclyl-C1-6-alkyl, aryl-C1-6-alkoxy, heteroaryl-C1-6-alkoxy, heterocyclyl-C1-6-alkoxy, C1-6-alkylamino, S1-6-dialkylamino, S1-6-alkyl, C3-8-cycloalkyl or is a group containing one or more of these components, each of these components can be optionally substituted R1e, C1-10-alkyl, HE, OR1e, OCOR1e, SH, SR1e, SCOR1e, NH2, NHR1e, NR1eR1f, COR1e, CSR1e, CN, COO,
COOR1e, CONH2, SO2R1e, SO3H, SO2NH2, CONR1eR1f, SO2NR1eR1f where R1e and R1f are independently selected from C1-6of alkyl, substituted C1-6-alkyl, C3-8-cycloalkyl and heterocyclyl, and R1e and R1f together with the adjacent heteroatom, can form heterocyclyl, provided that R1 and R2 both denote H, or

R1 and R2 together with N to which they are attached, can form a heteroaryl or heterocyclyl group, each of which may be optionally substituted by one or more groups selected from hydroxy, aryl, heteroaryl, partially or fully saturated heterocyclyl, S3-8-cycloalkyl, S1-6-alkyl, aryl-C1-6-alkyl, heteroaryl-C1-6-alkyl, heterocyclyl-C1-6-alkyl, C3-8-cycloalkyl-C1-6-alkyl, C1-6-alkoxy, aryloxy, heteroaromatic, heterocyclic, R2a, halogen, HE, OR2a, SH, SR2a, OCOR2a, SCOR2a, NH2, NHR2a, NR2aR2b, COR2a, CSR2a, CN, COOH, COOR2a, CONH2, SO2R2a, SO3H, SO2NH2, CONR2aR2b, SO2NR2aR2b, where R2a and R2b are independently selected from C1-6of alkyl, substituted C1-6-alkyl, C3-8-cycloalkyl and heterocyclyl, and R2a and R2b together with the adjacent heteroatom, can form heterocyclyl,

where, when the Deputy of heteroaryl or heterocyclyl formed by using both of R1 and R2 represents aryl, heteroaryl, heterocyclyl, sub>
3-8-cycloalkyl, S1-6-alkyl, aryl-C1-6-alkyl, heteroaryl-C1-6-alkyl, heterocyclyl-C1-6-alkyl, C3-8-cycloalkyl-C1-6-alkyl, C1-6-alkoxy, aryloxy, heteroaromatic, heterocyclic, or a group containing one or more of these components, each of these components can be optionally substituted by one group selected from halogen, hydroxyl, C1-6of alkyl, aryl, heteroaryl, heterocyclyl, S3-8-cycloalkyl, S1-4-alkoxy, aryloxy, heteroaromatic, heterocyclic, S3-8-cycloalkane, aryl-C1-4-alkoxy, heteroaryl-C1-4-alkoxy, heterocyclyl-C1-4-alkoxy, C3-8-cycloalkyl-C1-4-alkoxy, R2c, OR2c, SH, SR2c, OCOR2c, SCOR2c, NH2, NHR2c, NR2cR2d, COR2c, CSR2c, CN, COOH, COOR2c, CONH2, SO2R2c, - SO3H, SO2NH2, CONR2cR2d, SO2NR2cR2d, where R2c and R2d are independently selected from C1-6of alkyl, substituted C1-6-alkyl, C3-8-cycloalkyl and heterocyclyl, and R2c and R2d, together with the adjacent heteroatom, can form heterocyclyl,

where, when Deputy Deputy heteroaryl or heterocyclyl from both of R1 and R2 represents C1-4-alkyl, aryl, heteroaryl, heterocyclyl, S3-8-cycloalkyl, S1-4-alkoxy, aryloxy, heteroaromatic, heterocyclic, S3-8-cycloalkane, aryl-C1-4-alkoxy, heteroaryl-sub>
1-4-alkoxy, heterocyclyl-C1-4-alkoxy, C3-8-cycloalkyl-C1-4-alkoxy, or a group containing one or more of these components, each of these components can be optionally substituted C1-4-alkoxy, R2e, halogen, HE, OR2e, SH, SR2e, OCOR2e, SCOR2e, NH2, NHR2e, NR2eR2f, COR2e, CSR2e, CN, COOH, COOR2e, CONH2, SO2R2e, SO3H, SO2NH2, CONR2eR2f, SO2NR2eR2f where R2e and R2f are independently selected from C1-6of alkyl, substituted C1-6-alkyl, C3-8-cycloalkyl and heterocyclyl, and R2e and R2f together with the adjacent heteroatom, can form heterocyclyl;

ring A is selected from aryl, heteroaryl and heterocyclyl components, each of which may be optionally substituted by one or more groups selected from halogen, C1-6-alkyl, hydroxyl, aryl, heteroaryl, heterocyclyl, S1-6-alkoxy, aryloxy, heteroaromatic, heterocyclic, Ra, S1-10-alkyl, HE, ORa, OCORa, SH, SRa, SCORa, NH2, NHRa, NRaRb, CORa, CSRa, CN, COOH, COORa, CONH2, SO2Ra, SO3H, SO2NH2, CONRaRb, SO2NRaRb, wherein Ra and Rb are independently selected from C1-6of alkyl, substituted C1-6-alkyl, C3-8-cycloalkyl and heterocyclyl, and Ra and Rb together with the adjacent heteroatom, can form heterocyclyl,

where, when ring A is substituted C1-6the alkyl, aryl, heteroaryl, heterocyclyl, S1-6
-alkoxy, aryloxy, heteroaromatic, heterocyclic, C1-10-alkyl, C3-8-cycloalkyl, or substituted by a group containing one or more of these components, each of these components can be optionally substituted with Rc, C1-10-alkyl, HE, ORc, OCORc, SH, SRc, SCORc, NH2, NHRc, NRcRd, CORc, CSRc, CN, COOH, COORc, CONH2, SO2Rc, SO3H, SO2NH2, CONRcRd, SO2NRcRd, where Rc and Rd are independently selected from C1-6of alkyl, substituted C1-6-alkyl, C3-8-cycloalkyl and heterocyclyl, and Rc and Rd together with the adjacent heteroatom, can form heterocyclyl;

where, when the Deputy R3 mean C1-10-alkyl, aryl, heteroaryl, heterocyclyl, S1-6-alkoxy, aryloxy, heteroaromatic, heterocyclic, S1-6-alkyl, C3-8-cycloalkyl, or means a group containing one or more of these components, each of these components can be optionally substituted by R3e, S1-10-alkyl, HE, OR3e, OCOR3e, SH, SR3e, SCOR3e, NH2, NHR3e, NR3eR3f, COR3e, CSR3e, CN, COOH, COOR3e, CONH2, SO2R3e, SO3H, SO2NH2, CONR3eR3f, SO2NR3eR3f where R3e and R3f are independently selected from C1-6of alkyl, substituted C1-6-alkyl, C3-8-cycloalkyl and heterocyclyl, and R3e and R3f, together with the adjacent heteroatom, can form heterocyclyl;

where, when R4 mean C1-10-alkyl, aryl, heteroaryl, heterocyclyl, S1-6-alkoxy, aryloxy, heteroaromatic, heterocyclic, S1-6-alkyl, C3-8-cycloalkyl, or means a group containing one or more of these components, each of these components can be optionally substituted by aryl, heteroaryl, heterocyclyl, S1-6-alkoxy, aryloxy, heteroaromatic, heterocyclic, R4c, C1-10-alkyl, HE, OR4c, OCOR4c, SH, SR4c, SCOR4c, NH2, NHR4c, NR4cR4d, COR4c, CSR4c, CN, COOH, COOR4c, CONH2, SO2R4c, SO3H, SO2NH2, CONR4cR4d, SO2NR4cR4d, where R4c and R4d are independently selected from C1-6of alkyl, substituted C1-6-alkyl, C3-8-cycloalkyl and heterocyclyl, and R4c and R4d together with the adjacent heteroatom, can form heterocyclyl,

where, when the Deputy R4 mean C1-10-alkyl, aryl, heteroaryl, heterocyclyl, S1-6-alkoxy, aryloxy, heteroaromatic, heterocyclic, S1-6-alkyl, C3-8-cycloalkyl�,
or means a group containing one or more of these components, each of these components can be optionally substituted with R4e, C1-10-alkyl, HE, OR4e, OCOR4e, SH, SR4e, SCOR4e, NH2, NHR4e, NR4eR4f, COR4e, CSR4e, CN, COOH, COOR4e, CONH2, SO2R4e, SO3H, SO2NH2, CONR4eR4f, SO2NR4eR4f, where R4e and R4f are independently selected from C1-6of alkyl, substituted C1-6-alkyl, C3-8-cycloalkyl and heterocyclyl, and R4e and R4f together with the adjacent heteroatom, can form heterocyclyl;

where, when R5 mean C1-6-alkyl, aryl, heteroaryl, heterocyclyl, S1-6-alkoxy, aryloxy, heteroaromatic, heterocyclic, S1-6-alkyl, C3-8-cycloalkyl, or means a group containing one or more of these components, each of these components can be optionally substituted by aryl, heteroaryl, heterocycle�scrap,
With1-6-alkoxy, aryloxy, heteroaromatic, heterocyclic, R5c, C1-6-alkyl, HE, OR5c, OCOR5c, SH, SR5c, SCOR5c, NH2, NHR5c, NR5cR5d, COR5c, CSR5c, CN, COOH, COOR5c, CONH2, SO2R5c, SO3H, SO2NH2, CONR5cR5d, SO2NR5cR5d where R5c and R5d are independently selected from C1-6of alkyl, substituted C1-6-alkyl, C3-8-cycloalkyl and heterocyclyl, and R5c and R5d together with the adjacent heteroatom, can form heterocyclyl,

where, when Deputy when R5 mean C1-6-alkyl, aryl, heteroaryl, heterocyclyl, S1-6-alkoxy, aryloxy, heteroaromatic, heterocyclic, S3-8-cycloalkyl, or means a group containing one or more of these components, each of these components can be optionally substituted with R5e, S1-6-alkyl, HE, OR5e, OCOR5e, SH, SR5e, SCOR5e, NH2, NHR5e, NR5eR5f, COR5e, CSR5e, CN, COOH, COOR5e, CONH2, SO2R5e, SO3H, SO2NH2, CONR5eR5f, SO2NR5eR5f, where R5e and R5f are independently selected from C1-6of alkyl, substituted C1-6-alkyl, C3-8-cycloalkyl and heterocyclyl, and R5e and R5f together with the adjacent heteroatom, can form heterocyclyl;

where, when Deputy R8 means With1-6-alkyl, aryl, heteroaryl, heterocyclyl, S1-6-alkoxy, aryloxy, heteroaromatic, heterocyclic, aryl-C1-6-alkyl, heteroaryl-C1-6-alkyl, heterocyclyl-C1-6-alkyl, aryl-C1-6-alkoxy, heteroaryl-C1-6-alkoxy, heterocyclyl-C1-6-alkoxy, C3-8-cycloalkyl, or means a group containing one or more of these components, each of these components can be optionally substituted by R8e, S1-6-alkyl, HE, OR8e, OCOR8e, SH, SR8e, SCOR8e, NH2, NHR8e, NR8eR8f, COR8e, CSR8e, CN, COOH, COOR8e, CONH2, SO2R8e, SO3H, SO2NH2, CONR8eR8f, SO2NR8eR8f where R8e and R8f are independently selected from C1-6of alkyl, substituted C1-6-alkyl, C3-8-cycloalkyl and heterocyclyl, and R8e and R8f, together with the adjacent heteroatom, can form heterocyclyl;

or their pharmaceutically acceptable salts or esters;

provided that when R1 and R2 together form piperidinyl in compounds of the form�s I,
piperidinyl not substituted bromide, dimetilan, ethyl, isopropyl, tert-butyl, trifluoromethyl sulfide, chlorine, bromine or benzyl,

provided that R1 and R2 together in compounds having formula I does not form a 6,7-dimethoxy-3,4-dihydro-1H-isoquinoline-2-yl, 6-methoxy-3,4-dihydro-1H-isoquinoline-2-yl, 7-methoxy-3,4-dihydro-1H-isoquinoline-2-yl, 7-amino-3,4-dihydro-1H-isoquinoline-2-yl, 7-nitro-3,4-dihydro-1H-isoquinoline-2-yl, 3,4-dihydro-1H-isoquinoline-2-yl, 3,4-dihydro-1H-isoquinoline-1-yl, 3,4-dihydro-2H-quinolin-1-yl, pyrrolidin-1-yl, 3,6-dihydro-2H-pyridin-1-yl, 8-Aza-Spiro[4.5]Dec-8-yl, 1,3-dihydroindol-2-yl, octahydrocyclopenta-2-yl, 1,2,6-triaza-Spiro[2.5]Oct-1-EN-6-yl or azepin-1-yl, and

provided that ring A in compounds having formula I does not form a pyridine, pyrazine, substituted pyridine or substituted pyrazine, when R1 and R2 together with N to which they are attached, form piperidinyl, piperazinyl, substituted piperidinyl or substituted piperazinyl.

In accordance with the following variant embodiment of the invention provides compounds having the formula I or formula II:

where, when R1 or R2 represents C1-20-alkyl, alkoxy, aryl, heteroaryl, heterocyclyl, S3-10-cycloalkyl, aryl-C1-6-alkyl, heteroaryl-C1-6-alkyl, heterocyclyl-C1-6-alkyl, C3-10-cycloalkyl-C1-6-alkyl, C1-6-alkyl, C3-8-cycloalkyl or is a group containing one or more of these components, each of these components can be optionally substituted by one or more groups selected from R1c, halogen, aryl, heteroaryl, heterocyclyl, C1-6-alkoxy, aryloxy, heteroaromatic, heterocyclic, aryl-C1-6-alkyl, heteroaryl-C1-6-alkyl, heterocyclyl-C1-6-alkyl, aryl-C1-6-alkoxy, heteroaryl-C1-6-alkoxy, heterocyclyl-C1-6-alkoxy, C1-6-alkylamine, C1-6-dialkylamino, C1-10-alkyl, HE, OR1c, OCOR1c, SH, SR1c, SCOR1c, NH2, NO2, NHR1c, NR1cR1d, COR1c, CSR1c, CN, COOH, COOR1c, CONH2, SO
2R1c, SO3H, SO2NH2, CONR1cR1d, SO2NR1cR1d, where R1c and R1d are independently selected from C1-6of alkyl, substituted C1-6of alkyl, aryl, heteroaryl, S3-8-cycloalkyl and heterocyclyl, or R1c and R1d, together with the heteroatom to which they are attached, can form heterocyclyl,

where, when Deputy when R1 or R2 means C1-10-alkyl, aryl, heteroaryl, heterocyclyl, C1-6-alkoxy, aryloxy, heteroaromatic, heterocyclic, aryl-C1-6-alkyl, heteroaryl-C1-6-alkyl, heterocyclyl-C1-6-alkyl, aryl-C1-6-alkoxy, heteroaryl-C1-6-alkoxy, heterocyclyl-C1-6-alkoxy, C1-6-alkylamino, C1-6-dialkylamino, C1-6-alkyl, C3-8-cycloalkyl or is a group containing one or more of these components, each of these components can be optionally substituted by one or more groups selected from R1e, halogen, C1-10-alkyl, HE, OR1e, OCOR1e, SH, SR1e, SCOR1e, NH2, NO2, NHR1e, NR1eR1f, COR1e, CSR1e, CN, COOH, COOR1e, CONH2, SO2R1e, SO3H, SO2NH2, CONR1eR1f, SO2NR1eR1f where R1e and R1f are independently selected from C1-6of alkyl, substituted C1-6of alkyl, aryl, heteroaryl, S3-8-cycloalkyl and heterocyclyl, or R1e and R1f together with the heteroatom to which they are attached, can form heterocyclyl,

provided that R, and R2 both denote H,

or

R1 and R2 together with N to which they are attached, can form a heteroaryl or heterocyclyl group, each of which may be optionally substituted by one or more oxygen atoms or one or more groups selected from hydroxy, aryl, heteroaryl, partially or fully saturated heterocyclyl, S3-8-cycloalkyl, C1-6-alkyl, aryl-C1-6-alkyl, heteroaryl-C1-6-alkyl, heterocyclyl-C1-6-alkyl, C3-8-cycloalkyl-C1-6-alkyl, C1-6-alkoxy, aryloxy, heteroaromatic, heterocyclic, R2a, halogen, HE, OR2a, SH, SR2a, OCOR2a, SCOR2a, NH2, NO2, NHR2a, NR2aR2b, COR2a, CSR2a, CN, COOH, COOR2a, CONH2, SO2R2a, SO3H, SO2NH2, CONR2aR2b, SO2NR2aR2b, where R2a and R2b are independently selected from C1-6of alkyl, substituted C1-6of alkyl, aryl, heteroaryl, S3-8-cycloalkyl and heterocyclyl, or R2a and R2b, together with the heteroatom to which they are attached, can form heterocyclyl,

where, when the Deputy of heteroaryl or heterocyclyl formed by using both of R1 and R2 represents aryl, heteroaryl, heterocyclyl, S3-8-cycloalkyl, C1-6-alkyl, aryl-C1-6-alkyl, heteroaryl-C1-6-alkyl, heterocyclyl-C1-6-alkyl, C3-8-cycloalkyl-C1-6-alkyl, C1-6-alkoxy, aryloxy, heteroaromatic, heterocyclic or group
containing one or more of these components, each of these components can be optionally substituted by one or more groups selected from halogen, hydroxyl, C1-6of alkyl, aryl, heteroaryl, heterocyclyl, S3-8-cycloalkyl, C1-4-alkoxy, aryloxy, heteroaromatic, heterocyclic, S3-8-cycloalkane, aryl-C1-4-alkoxy, heteroaryl-C1-6-alkoxy, heterocyclyl-C1-4-alkoxy, C3-8-cycloalkyl-C1-4-alkoxy, R2c, OR2c, SH, SR2c, OCOR2c, SCOR2c, NH2, NO2, NHR2c, NR2cR2d, COR2c, CSR2c, CN, COOH, COOR2c, CONH2, SO2R2c, - SO3H, SO2NH2, CONR2cR2d, SO2NR2cR2d, where R2c and R2d are independently selected from C1-6of alkyl, substituted C1-6of alkyl, aryl, heteroaryl, S3-8-cycloalkyl and heterocyclyl, or R2c and R2d, together with the heteroatom to which they are attached, can form heterocyclyl,

where, when Deputy Deputy heteroaryl or heterocyclyl formed by using both of R1 and R2 represents C1-6-alkyl, aryl, heteroaryl, heterocyclyl, S3-8-cycloalkyl, C1-6-alkoxy, aryloxy, heteroaromatic, heterocyclic, S3-8-cycloalkane, aryl-C1-4-alkoxy, heteroaryl-C1-4-alkoxy, heterocyclyl-C1-4-alkoxy, C3-8-cycloalkyl-C1-4-alkoxy, or is a group containing one or bol�e of these components,
each of these components can be optionally substituted by one or more groups selected from C1-4-alkoxy, R2e, halogen, HE, OR2e, SH, SR2e, OCOR2e, SCOR2e, NH2, NO2, NHR2e, NR2eR2f, NHCOR2e, COR2e, CSR2e, CN, COOH, COOR2e, CONH2, SO2R2e, SO3H, SO2NH2, CONR2eR2f, SO2NR2eR2f where R2e and R2f are independently selected from Ci-6-alkyl, substituted C1-6of alkyl, aryl, heteroaryl, S3-8-cycloalkyl and heterocyclyl, or R2e and R2f, together with the heteroatom to which they are attached, can form heterocyclyl;

ring A is selected from aryl, heteroaryl and heterocyclyl components, each of which may be optionally substituted by one or more groups selected from halogen, C1-6-alkyl, hydroxyl, aryl, heteroaryl, heterocyclyl, C1-6-alkoxy, aryloxy, heteroaromatic, heterocyclic, Ra, S1-10-alkyl, HE, ORa, OCORa, SH, SRa, SCORa, NH2, NO2, NHRa, NRaRb, CORa, CSRa, CN, COOH, COORa, CONH2, CONHOH, CONHORa, SO2Ra, SO3H, SO2NH2, CONRaRb, SO2NRaRb, wherein Ra and Rb are independently selected from C1-6of alkyl, substituted C1-6of alkyl, aryl, heteroaryl, S3-8-cycloalkyl and heterocyclyl, or Ra and Rb, together with the heteroatom to which they are attached, can form heterocyclyl,

where, when ring A is substituted C1-6the alkyl, aryl, heteroaryl, heterocyclyl, C1-6alkoxy,
aryloxy, heteroaromatic, heterocyclic, C1-10-alkyl, C3-8-cycloalkyl, or substituted by a group containing one or more of these components, each of these components can be optionally substituted by one or more groups selected from halogen, Rc, S1-10-alkyl, aryl-C1-6-alkyl, HE, ORc, OCORc, SH, SRc, SCORc, NH2, NO2, NHRc, NRcRd, CORc, CSRc, CN, COOH, COORc, CONH2, SO2Rc, SO3H, SO2NH2, CONRcRd, SO2NRcRd, where Rc and Rd are independently selected from C1-6of alkyl, substituted C1-6of alkyl, aryl, heteroaryl, S3-8-cycloalkyl and heterocyclyl, or Rc and Rd together with the heteroatom to which they are attached, can form heterocyclyl;

where, when R3 means With1-10-alkyl, aryl, heteroaryl, hetero�iklil,
C1-6-alkoxy, aryloxy, heteroaromatic, heterocyclic, C1-6-alkyl, C3-8-cycloalkyl, or means a group containing one or more of these components, each of these components can be optionally substituted by one or more groups selected from halogen, aryl, heteroaryl, heterocyclyl, C1-6-alkoxy, aryloxy, heteroaromatic, heterocyclic, R3c, C1-10-alkyl, HE, OR3c, OCOR3c, SH, SR3c, SCOR3c, NH2, NO2, NHR3c, NR3cR3d, COR3c, CSR3c, CN, COOH, COOR3c, CONH2, SO2R3c, SO3H, SO2NH2, CONR3cR3d, S02NR3cR3d where R3c and R3d are independently selected from C1-6of alkyl, substituted C1-6of alkyl, aryl, heteroaryl, S3-8-cycloalkyl and heterocyclyl, or R3c and R3d, together with the heteroatom to which they are attached, can form heterocyclyl,

where, when Deputy when R3 means With1-10-alkyl, aryl, heteroaryl, heterocyclyl, C1-6alkoxy, aryloxy, heteroaromatic, heterocyclic, C1-6-alkyl, C3-8-cycloalkyl, or means a group containing one or more of these components, each of these components can be optionally substituted by one or more groups selected from halogen, R3e, S1-10-alkyl, HE, OR3e, OCOR3e, SH, SR3e, SCOR3e, NH2, NO2, NHR3e, NR3eR3f, COR3e, CSR3e, CN, COOH, COOR3e, CONH2, SO2R3e, SO3H, SO2NH2, CONR3eR3f, SO2NR3eR3f where R3e and 3f are independently selected from C
1-6of alkyl, substituted C1-6of alkyl, aryl, heteroaryl, S3-8-cycloalkyl and heterocyclyl, or R3e and R3f, together with the heteroatom to which they are attached, can form heterocyclyl;

where, when R4 mean C1-10-alkyl, aryl, heteroaryl, heterocyclyl, C1-6-alkoxy, aryloxy, heteroaromatic, heterocyclic, C1-6-alkyl, C3-8-cycloalkyl, or means a group containing one or more of these components, each of these components can be optionally substituted by one or more groups selected from halogen, aryl, heteroaryl, heterocyclyl, C1-6-alkoxy, aryloxy, heteroaromatic, heterocyclic, R4c, C1-10-alkyl, HE, OR4c, OCOR4c, SH, SR4c, SCOR4c, NH2, NO2, NHR4c, NR4cR4d, COR4c, CSR4c, CN, COOH, COOR4c, CNH
2, SO2R4c, SO3H, SO2NH2, CONR4cR4d, SO2NR4cR4d, where R4c and R4d are independently selected from C1-6of alkyl, substituted C1-6of alkyl, aryl, heteroaryl, S3-8-cycloalkyl and heterocyclyl, or R4c and R4d, together with the heteroatom to which they are attached, can form heterocyclyl,

where, when Deputy when R4 mean C1-10-alkyl, aryl, heteroaryl, heterocyclyl, C1-6-alkoxy, aryloxy, heteroaromatic, heterocyclic, C1-6-alkyl, C3-8-cycloalkyl, or means a group containing one or more of these components, each of these components can be optionally substituted by one or more groups selected from halogen, R4e, C1-10-alkyl, HE, OR4e, OCOR4e, SH, SR4e, SCOR4e, NH2, NO2, NHR4e, NR4eR4f, COR4e, CSR4e, CN, COOH, COOR4e, CONH2, SO2R4e, SO3H, SO2NH2, CONR4eR4f, SO2NR4eR4f, where R4e and R4f are independently selected from C1-6of alkyl, substituted C1-6of alkyl, aryl, heteroaryl, S3-8-cycloalkyl and heterocyclyl, or R4e and R4f, together with the heteroatom to which they are attached, can form heterocyclyl;

where, when R5 mean C1-6-alkyl, aryl, heteroaryl, heterocyclyl, C1-6-alkoxy, aryloxy, heteroaromatic, heterocyclic, C1-6-alkyl, C3-8-cycloalkyl, or means a group containing one or more of these components, each of these components can be optionally substituted by one or more groups selected from halogen, aryl, heteroaryl, heterocyclyl, C1-6-alkoxy, aryloxy, heteroaromatic, heterocyclic, R5c, C1-6-alkyl, HE, OR5c, OCOR5c, SH, SR5c, SCOR5c, NH2, NO2, NHR5c, NR5cR5d, COR5c, CSR5c, CN, COOH, COOR5c, CONH2, SO2R5c, SO3H, SO2NH2, CONR5cR5d, SO2NR5cR5d where R5c and R5d are independently selected from C1-6of alkyl, substituted C1-6of alkyl, aryl, heteroaryl, S3-8-cycloalkyl and heterocyclyl, or R5c and R5d, together with the heteroatom to which they are attached, can form heterocyclyl,

where, when Deputy when R5 mean C1-6-alkyl, aryl, heteroaryl, heterocyclyl, C1-6-alkoxy, aryloxy, heteroaromatic, heterocyclic, S3-8-C�cloaker,
or means a group containing one or more of these components, each of these components can be optionally substituted by one or more groups selected from halogen, R5e, C1-6-alkyl, HE, OR5e, OCOR5e, SH, SR5e, SCOR5e, NH2, NO2, NHR5e, NR5eR5f, COR5e, CSR5e, CN, COOH, COOR5e, CONH2, SO2R5e, SO3H, SO2NH2, CONR5eR5f, SO2NR5eR5f, where R5e and R5f are independently selected from C1-6of alkyl, substituted C1-6of alkyl, aryl, heteroaryl, S3-8-cycloalkyl and heterocyclyl, or R5e and R5f, together with the heteroatom to which they are attached, can form heterocyclyl;

where, when R6 means heteroaryl or heterocyclyl, each of these components can optionally be substituted by one or more oxygen atoms, and when R6 means C1-6-Alki�,
aryl, heteroaryl, heterocyclyl, C1-6-alkoxy, aryloxy, heteroaromatic, heterocyclic, S3-8-cycloalkyl, or means a group containing one or more of these components, each of these components can be optionally substituted by one or more groups selected from halogen, R6c, C1-6-alkyl, C1-6-alkynyl, aryl, heteroaryl, heterocyclyl, C1-6-alkoxy, aryloxy, heteroaromatic, heterocyclic, aryl-C1-6-alkyl, heteroaryl-C1-6-alkyl, heterocyclyl-C1-6-alkyl, aryl-C1-6-alkoxy, heteroaryl-C1-6-alkoxy, heterocyclyl-C1-6-alkoxy, HE, OR6c, OCOR6c, SH, SR6c, SCOR6c, NH2, NO2, NHR6c, NR6cR6d, COR6c, CSR6c, CN, COOH, COOR6c, CONH2, CONHOH, C(NOH)NH2, SO2R6c, SO3H, SO2NH2, CONR6cR6d, SO2NR6cR6d where R6c and R6d are independently selected from C1-6of alkyl, substituted C1-6of alkyl, aryl, heteroaryl, S3-8-cycloalkyl and heterocyclyl, or R6c and R6d, together with the heteroatom to which they are attached, can form heterocyclyl,

where, when Deputy from R6 means heteroaryl or heterocyclyl, each of these components can optionally be substituted by one or more oxygen atoms, or when the Deputy when R6 means C1-6-alkyl, C1-6-alkynyl, aryl, heteroaryl, heterocyclyl, C1-6-alkoxy, aryloxy, heteroaryl�si
heterocyclics, aryl-C1-6-alkyl, heteroaryl-C1-6-alkyl, heterocyclyl-C1-6-alkyl, aryl-C1-6-alkoxy, heteroaryl-C1-6-alkoxy, heterocyclyl-C1-6-alkoxy, C3-8-cycloalkyl, or means a group containing one or more of these components, each of these components can be optionally substituted by one or more groups selected from halogen, R6e, C1-6-alkyl, C1-4-alkoxy, HE, OR6e, OCOR6e, SH, SR6e, SCOR6e, NH2, NO2, NHR6e, NR6eR6f, COR6e, CSR6e, CN, COOH, COOR6e, CONH2, C(NOH)NH2, SO2R6e, SO3H, SO2NH2, CONR6eR6f, SO2NR6eR6f where R6e and R6f are independently selected from C1-6of alkyl, substituted C1-6of alkyl, aryl, heteroaryl, S3-8-cycloalkyl and heterocyclyl, or R6e and R6f, together with the heteroatom to which they are attached, can form heterocyclyl;

where, when R7 means heteroaryl or heterocyclyl, each of these components can optionally be substituted by one or more oxygen atoms, and when R7 mean C1-6-alkyl, aryl, heteroaryl, heterocyclyl, C1-6-alkoxy, aryloxy, heteroaromatic, heterocyclic, S3-8-cycloalkyl, or means a group containing one or more of these components, each of these components can be optionally substituted by one or more groups selected from halogen, R7c, C1-6-alkyl, C1-6-alkynyl, aryl, heteroaryl, heterocyclyl, C1-6-alkoxy, aryloxy, heteroaromatic, heterocyclic, aryl-C1-6-alkyl, heteroaryl-C1-6-alkyl, heterocyclyl-C1-6-alkyl, aryl-C1-6-alkoxy, heteroaryl-C1-6-alkoxy, heterocyclyl-C1-6-alkoxy, HE, O7c, OCOR7c, SH, SR7c, SCOR7c, NH2, NO2, NHR7c, NR7cR7d, COR7c, CSR7c, CN, COOH, COOR7c, CONH2, CONHOH, C(NOH)NH2, SO2R7c, SO3H, SO2NH2, CONR7cR7d, SO2NR7cR7d where R7c and R7d are independently selected from C1-6of alkyl, substituted C1-6of alkyl, aryl, heteroaryl, S3-8-cycloalkyl and heterocyclyl, or R7c and R7d, together with the heteroatom to which they are attached, can form heterocyclyl,

where, when Deputy R7 means heteroaryl or heterocyclyl, each of these SOS�alausa can optionally be substituted by one or more oxygen atoms,
and when the Deputy when R7 mean C1-6-alkyl, C1-6-alkynyl, aryl, heteroaryl, heterocyclyl, C1-6-alkoxy, aryloxy, heteroaromatic, heterocyclic, aryl-C1-6-alkyl, heteroaryl-C1-6-alkyl, heterocyclyl-C1-6-alkyl, aryl-C1-6-alkoxy, heteroaryl-C1-6-alkoxy, heterocyclyl-C1-6-alkoxy, C3-8-cycloalkyl, or means a group containing one or more of these components, each of these components can be optionally substituted by one or more groups selected from halogen, aryl, heteroaryl, heterocyclyl, aryl-C1-6-alkyl, heteroaryl-C1-6-alkyl, heterocyclyl-C1-6-alkyl, C1-4-alkoxy, R7e, C1-6-alkyl, HE, OR7e, OCOR7e, SH, SR7e, SCOR7e, NH2, NO2, NHR7e, NR7eR7f, COR7e, CSR7e, CN, COOH, COOR7e, CONHz, C(NOH)NH2, SO2R7e, SO3H, SO2NH2, CONR7eR7f, SO2NR7eR7f where R7e and R7f are independently selected from C1-6of alkyl, substituted C1-6of alkyl, aryl, heteroaryl, S3-8-cycloalkyl and heterocyclyl, or R7e and R7f, together with the heteroatom to which they are attached, can form heterocyclyl;

where, when R8 means C1-6-alkyl, C1-10-alkyl, aryl, heteroaryl, heterocyclyl, C1-6alkoxy, aryloxy, heteroaromatic, heterocyclic, S3-8-cycloalkyl, or means a group containing one or more of these components, each of these components can be optionally substituted by one or more groups selected from halogen, R8c, C1-6of alkyl, aryl, heteroaryl, heterocyclyl, C1-6-alkoxy, aryloxy, heteroaromatic, heterocyclic, aryl-C1-6-alkyl, heteroaryl-C1-6-alkyl, heterocyclyl-C1-6-alkyl, aryl-C1-6-alkoxy, heteroaryl-C1-6-alkoxy, heterocyclyl-C1-6-alkoxy, HE, OR8c, OCOR8c, SH, SR8c, SCOR8c, NH2, NO2, NHR8c, NR8cR8d, COR8c, CSR8c, CN, COOH, COOR8c, CONH2, SO2R8c, SO3H, SO2NH2, CONR8cR8d, SO2NR8cR8d, where R8c and R8d are independently selected from C1-6of alkyl, substituted C1-6of alkyl, aryl, heteroaryl, S3-8-cycloalkyl and heterocyclyl, or R8c and R8d, together with the heteroatom to which they are attached, can images�VAT heterocyclyl,

where, when Deputy R8 means C1-6-alkyl, aryl, heteroaryl, heterocyclyl, C1-6-alkoxy, aryloxy, heteroaromatic, heterocyclic, aryl-C1-6-alkyl, heteroaryl-C1-6-alkyl, heterocyclyl-C1-6-alkyl, aryl-C1-6-alkoxy, heteroaryl-C1-6-alkoxy, heterocyclyl-C1-6-alkoxy, C3-8-cycloalkyl, or means a group containing one or more of these components, each of these components can be optionally substituted by one or more groups selected from halogen, R8e, C1-6-alkyl, HE, OR8e, OCOR8e, SH, SR8e, SCOR8e, NH2, NO2, NHR8e, NR8eR8f, COR8e, CSR8e, CN, COOH, COOR8e, CONH2, SO2R8e, SO3H, SO2NH2, CONR8eR8f, SO2NR8eR8f where R8e and R8f are independently selected from C1-6of alkyl, substituted C1-6of alkyl, aryl, heteroaryl, S3-8-cycloalkyl and heterocyclyl, or R8e and R8f, together with the heteroatom to which they are attached, can form heterocyclyl;

where, at most, two atoms or groups denoted X, Y and Z can represent N;

where W stands for N, CONR1R2 group can be attached instead of W with the corresponding rearrangement of double bonds in formula I;

or their pharmaceutically acceptable salts or esters;

provided that when R1 and R2 together form piperidinyl in the compounds of formula I, piperidinyl not substituted methyl�m,
dimetilan, ethyl, isopropyl, tert-butyl, methoxycarbonyl, trifluoromethyl sulfide, chlorine, bromine or benzyl,

provided that R1 and R2 together in compounds having formula I does not form a 6,7-dimethoxy-3,4-dihydro-1H-isoquinoline-2-yl, 6-methoxy-3,4-dihydro-1H-isoquinoline-2-yl, 7-methoxy-3,4-dihydro-1H-isoquinoline-2-yl, 7-amino-3,4-dihydro-1H-isoquinoline-2-yl, 7-nitro-3,4-dihydro-1H-isoquinoline-2-yl, 3,4-dihydro-1H-isoquinoline-2-yl, 3,4-dihydro-1H-isoquinoline-1-yl, 3,4-dihydro-2H-quinolin-1-yl, pyrrolidin-1-yl, 3,6-dihydro-2H-pyridin-1-yl, 8-Aza-Spiro[4.5]Dec-8-yl, 1,3-dihydroindol-2-yl, octahydrocyclopenta-2-yl, 1,2,6-triaza-Spiro[2.5]Oct-1-EN-6-yl or azepin-1-yl, and

provided that ring A in compounds having formula I does not form a pyridine, pyrimidine, substituted pyridine or substituted pyrimidine, when R1 and R2 together with N to which they are attached, form piperidinyl, piperazinyl, substituted piperidinyl or substituted piperazinyl.

Preferably, the compounds of the invention have a formula selected from formula I, formula IIa, formula IIb, formula IIc and formula IId.

More preferably, the compounds of the invention have a formula selected from formula Ia, formula IIa, formula IIb, formula IIc and formula IId.

In one of the embodiments of the invention, R1 is preferably selected from H and C1-4
-alkyl. More preferably, R1 is selected from H and C1-3-alkyl, even more preferably, R1 is selected H, methyl and ethyl, and most preferably, R1 is selected from H and methyl.

R2 is preferably selected from C1-4of alkyl, aryl, heteroaryl, heterocyclyl, S3-10-cycloalkyl, aryl-C1-6-alkyl, heteroaryl-C1-6-alkyl, heterocyclyl-C1-6-alkyl and C3-10-cycloalkyl-C1-6-alkyl, each of which may be substituted or unsubstituted. Preferably, the aryl, heteroaryl, heterocyclyl and C3-10-cycloalkyl (including, included in the aryl-C1-6-alkyl, heteroaryl-C1-6-alkyl, heterocyclyl-C1-6-alkyl and C3-10-cycloalkyl-C1-6-alkyl) have 6-membered monocyclic ring structure. More preferably, the aryl, heteroaryl, heterocyclyl and C3-10-cycloalkyl (including, included in the aryl-C1-6-alkyl, heteroaryl-C1-6-alkyl, heterocyclyl-C1-6-alkyl and C3-10-cycloalkyl-C1-6-alkyl is selected from phenyl, cyclohexyl, phenyl-C1-6-alkyl and cyclohexyl-C1-6-alkyl, each of which may be substituted or unsubstituted. Preferably, C1-6-alkyl each of the aryl-C1-6-alkyl, heteroaryl-C1-6-alkyl, heterocyclyl-C1-6-alkyl and C3-10-cycloalkyl-C1-6-alkyl is a linear alkyl.

Alternative prices. e�tive,
R2 may be selected from aryl, heteroaryl, heterocyclyl, aryl-C1-6-alkyl, heteroaryl-C1-6-alkyl and heterocyclyl-C1-6-alkyl, each of which may be substituted or unsubstituted, and where the aryl, heteroaryl and heterocyclyl (including, included in the aryl-C1-6-alkyl, heteroaryl-C1-6-alkyl and heterocyclyl-C1-6-alkyl) have a bicyclic ring structure, preferably 10-membered bicyclic ring structure. More preferably, R2 is selected from naphthalenyl and naphthalenyl-C1-6-alkyl.

Each group R2 is selected from aryl, heteroaryl, heterocyclyl and C3-10cycloalkyl (including, included in the aryl-C1-6-alkyl, heteroaryl-C1-6-alkyl, heterocyclyl-C1-6-alkyl and C3-10-cycloalkyl-C1-6-alkyl) may be substituted by one or more Halogens.

Alternatively, each of the groups aryl, heteroaryl, heterocyclyl and C3-10-cycloalkyl (including, included in the aryl-C1-6-alkyl, heteroaryl-C1-6-alkyl, heterocyclyl-C1-6-alkyl and C3-10-cycloalkyl-C1-6-alkyl) may be substituted C1-4-alkoxy or aryloxy. Preferably, S1-4-alkoxy represents methoxy or ethoxy. Preferably, aryloxy is motickleysky aryloxy, and, more preferably, phenoxy.

In a preferred embodiment the OSU�of estline of the invention,
R1 is selected from H and C1-4-alkyl, and R2 is selected from aryl, heteroaryl, heterocyclyl, S3-10-cycloalkyl, aryl-C1-6-alkyl, heteroaryl-C1-6-alkyl, heterocyclyl-C1-6-alkyl and C3-10-cycloalkyl-C1-6-alkyl, each of which may be substituted or unsubstituted. More preferably, R1 is selected from H, methyl and ethyl and R2 is selected from aryl, heteroaryl, heterocyclyl and C3-10-cycloalkyl, each of which may be substituted or unsubstituted. More preferably, R1 means methyl. More preferably, R2 is selected from aryl, heteroaryl, heterocyclyl and C5-8-cycloalkyl, all of which are monocyclic and may be substituted or unsubstituted. Even more preferably, R2 is selected from saturated heterocyclyl and C5-8-cycloalkyl, all of which are monocyclic and may be substituted or unsubstituted. When R2 is a monocyclic C5-8-cycloalkyl, it is preferably unsaturated. Preferably, R2 represents cyclohexyl, such as unsubstituted cyclohexyl. When R2 means a monocyclic saturated heterocyclyl, heterokonta mainly contains one heteroatom. Preferably, the heteroatom is a nitrogen atom or oxygen. More preferably, heterocyclyl assetselection,
such as piperidinyl or tetrahydropyranyl. If the heteroatom is an oxygen atom, heterocyclyl is preferably unsubstituted. If the heteroatom is a nitrogen atom, the nitrogen heteroatom may be substituted or unsubstituted. If the nitrogen heteroatom is substituted, it is preferably substituted by a group selected from C1-6of alkyl, aryl, heteroaryl, heterocyclyl, S3-10-cycloalkyl, aryl-C1-6-alkyl, heteroaryl-C1-6-alkyl, heterocyclyl-C1-6-alkyl and C3-10-cycloalkyl-C1-6-alkyl, each of which may be substituted or unsubstituted. More preferably, the nitrogen heteroatom is substituted by a group selected from C1-4-alkyl, aryl-C1-4-alkyl, heteroaryl-C1-4-alkyl, heterocyclyl-C1-4-alkyl and C5-8-cycloalkyl-C1-4-alkyl. More preferably, the nitrogen heteroatom is substituted by a group selected from aryl-C1-4-alkyl and heteroaryl-C1-4-alkyl, where aryl and heteroaryl are monocyclic, and, preferably, six-membered. Preferably, the nitrogen heteroatom is substituted by a group selected from phenyl-C1-2-alkyl and pyridyl-C1-2-alkyl. Preferably, the hetero-atom in said heterocyclic group is in position 4 relative to the position of the accession of heterocyclic groups R2, kasota urea.
When R1 and R2 are as defined in this paragraph, the compound preferably has the formula IIa. Preferably, when R1 and R2 are as defined in this paragraph, R6 signifies a substituted or unsubstituted aryl or heteroaryl, and, preferably, substituted or unsubstituted monocyclic aryl or heteroaryl. Monocyclic aryl or heteroaryl is preferably six-membered. In one of the embodiments of the invention, R6 signifies a substituted or unsubstituted aryl (such as phenyl), and, preferably, unsubstituted. In another embodiment of the invention, R6 signifies a substituted or unsubstituted heteroaryl and, preferably, substituted or unsubstituted pyridyl. In one of the embodiments of the invention, heteroaryl substituted oxygen atom. For example, the heteroatom nitrogen pyridyl can be replaced by an oxygen atom so that it is oxidized, i.e. formed N-oxide.

It was found that the compounds identified in the previous paragraph, the values of R1 and R2 show relatively high specificity for FAAH. In addition, it was found that compounds in which R2 represents heterocyclyl, such as piperidinyl or tetrahydropyranyl are relatively metabolically stable.

Alternatively, in other embodiments, when R1 means H and C1-4-alkyl; N and C1-3-Alki�;
H, methyl and ethyl; H and methyl; or methyl, R2 can be selected from aryl, heteroaryl, partially or fully saturated heterocyclyl, S3-10-cycloalkyl, aryl-C1-6-alkyl, heteroaryl-C1-6-alkyl, heterocyclyl-C1-6-alkyl, C3-10-cycloalkyl-C1-6-alcea, where R2 can be substituted or unsubstituted.

In a preferred embodiment of the invention, R1 and R2 together with N to which they are attached, form a heterocyclic group which may be substituted or unsubstituted. Preferably, heterocyclyl represents a 5 - or 6-membered monocyclic ring, and more preferably, 5-membered monocyclic ring. In some embodiments, the specified heterocyclyl contains one or two, preferably 1 additional heteroatom (i.e., in addition to N). These additional heteroatoms can be, for example, N, O and/or S. Preferably, heterocyclyl is oxazolidinyl. Preferably, the oxygen atom in oxazolidinyl is in position 3 relative to the nitrogen of urea. Preferably, oxazolidinyl substituted one, two or three methyl or ethyl groups. More preferably, oxazolidinyl substituted by two methyl or ethyl groups. Even more preferably, oxazolidinyl sameshe� two methyl groups at the same carbon atom.
More preferably, oxazolidinyl represents a 4,4-dimethyloxazolidine-3-yl. When R1 and R2 are as defined in this paragraph, the compound preferably has the formula Ia or IIa. Preferably, when R1 and R2 are as defined in this paragraph and the compound has the formula IIa, R6 is a substituted or unsubstituted aryl, and preferably phenyl. When R1 and R2 are as defined in this paragraph and the compound has the formula Ia, ring A preferably represents a substituted or unsubstituted benzo component.

It was found that compounds having values R1 and R2 defined in the previous paragraph are potential inhibitors of FAAH. It was also found that they have a relatively high selectivity for FAAH.

In an alternative embodiment, R1 and R2 together with N to which they are attached, form a heterocyclic group which may be substituted or unsubstituted. Preferably, heterocyclyl represents a 5 - or 6-membered monocyclic ring, more preferably, 6-membered monocyclic ring. Preferably, R1 and R2 together form morpholino, piperazinyl, oxazolidinyl, pyrrolidinyl or piperidinyl. More preferably, R1 and R2 together form a morpholino or piperazinyl.

Prefer�till then,
heterocyclyl, formed from R1 and R2 substituted C1-6the alkyl, aryl, heteroaryl, S3-8-cycloalkyl, aryl-C1-6-alkyl, heteroaryl-C1-6-alkyl, aryloxy, heteroaromatic, aryl-C1-6-alkoxy and heteroaryl-C1-6-alkoxy, each of which may be optionally substituted by one or more Halogens or C1-4-alkyl. Preferably, Deputy aryl, heteroaryl or C3-8cycloalkyl represents a 5 - or 6-membered motyklejskoe ring. More preferably, heterocyclyl, formed from R1 and R2, substituted aryl, aryl-C1-6the alkyl and aryloxy, each of which may be optionally substituted by one or more Halogens. Even more preferably, heterocyclyl, formed from R1 and R2 substituted phenyl, phenyl-C1-6-alkyl or phenoxy, each of which may be optionally substituted by one or more Halogens.

Alternative, heterocyclyl, formed from R1 and R2, can be replaced by heteroaryl or heteroaryl-C1-6-alkyl. In one of the embodiments of the invention, heteroaryl has a bicyclic ring structure, for example, benzodioxolyl. Alternatively, heteroaryl may be monocyclic, for example, pyridyl.

In another alternative, heterocyclyl, formed from R1 and R2, can be substituted With3-8-cycloalkyl. Preferably�individual,
With3-8-cycloalkyl represents a monocyclic cycloalkyl, such as cyclohexyl.

In one of the embodiments of the invention, heterocyclyl, formed from R1 and R2 may represent a 1,4-dioxa-8 azaspiro[4.5]Dec-8-yl, dimethoxyquinazoline, methylpiperazine, benzyloxyaniline, triacetyluridine, pyrrolidinyl1-4-the alkyl piperidinyl, paradiseparadise, pyridylacetate-5-ipipeline or benzyloxypyridine.

In one of the embodiments of the invention, heterocyclyl, formed from R1 and R2 represents piperidinyl, substituted phenoxy, or phenyl-C1-4-alkoxy, and where phenyl may be optionally substituted by halogen.

In one of the embodiments of the invention, when V mean C-R3, R3 means H or halogen.

In another embodiment of the invention, when W stands for C-R4, R4 is selected from H and aryl. Preferably, R4 is selected from H and phenyl. More preferably, R4 means H.

In the compounds according to the invention the ring And preferably represents a substituted or unsubstituted monocyclic aryl or heteroaryl component, and more preferably, a monocyclic aryl component. Preferably, ring A is a substituted or unsubstituted benzo component. When monocyclic� aryl ring And is substituted,
Deputy represents one or more halogen, C1-6-alkyl or aryl that may be optionally substituted by one or more Halogens, cyano, carboxylic acid or amide. Preferably, Deputy aryl is a monocyclic aryl, and preferably phenyl. In a preferred embodiment of the invention, the compound having the ring A, as defined in this paragraph, has the formula Ia.

In one of the embodiments of the invention, ring A is substituted with a component selected from C1-6-alkoxy, C1-6-alkoxy-C1-6-alkyl and C0-6-alkyl-CO-C0-6-alkyl, where C1-6-alkoxy, C1-6-alkoxy-C1-6-alkyl or C0-6-alkyl-CO-C0-6-alkyl substituted with a component selected from aryl, heteroaryl, heterocyclyl and C3-10-cycloalkyl, where each of these components can be optionally substituted by aryl, heteroaryl, heterocyclyl, S3-10-cycloalkyl, aryl-C1-6-alkyl, heteroaryl-C1-6-alkyl, heterocyclyl-C1-6-alkyl, and C3-10-cycloalkyl-C1-6-alkyl. Preferably, ring A is substituted C0-6-alkyl-CO-C0-6-alkyl, where C0-6-alkyl-CO-C0-6-alkyl substituted with a component selected from aryl, heteroaryl, heterocyclyl and C3-10-cycloalkyl, where each of these amounted to�of governors may be optionally substituted by aryl,
heteroaryl, heterocyclyl, S3-10-cycloalkyl, aryl-C1-6-alkyl, heteroaryl-C1-6-alkyl, heterocyclyl-C1-6-alkyl, and C3-10-cycloalkyl-C1-6-alkyl. Preferably, ring A is substituted with a carbonyl component (i.e., C0-alkyl-CO-C0-alkyl). Preferably, S0-6-alkyl-CO-C0-6-alkyl substituted by heterocyclyl, more preferably, a monocyclic heterocyclyl, even more preferably, heterocyclyl containing one or two heteroatom of nitrogen, even more preferably, six-membered heterocyclyl, and most preferably piperazine. Preferably, C1-6-alkoxy, C1-6-alkoxy-C1-6-alkyl and C0-6-alkyl-CO-C0-6-alkyl are linear. Preferably, the compounds described in this paragraph, are compounds of the formula Ia.

Preferably, in compounds according to the invention, R5 means H or halogen, and, more preferably, R5 means H.

In one of the embodiments of the invention, R5 together with the ring carbon atom to which it is attached, forms a carbonyl group. The compound is a compound of formula II, above.

In another embodiment of the invention, X is not O. means the Compound is a compound of formula II, above.

In compounds having formula II, when X is C-R6, R6 preferably means substituted or unsubstituted aryl. Preferably, R6 is aryl represents phenyl or naphthalenyl. More preferably, R6 is aryl represents phenyl. Preferably, R6 is aryl substituted by one or more groups selected from halogen, C1-4-alkoxy, hydroxyl, amide, aryl, heterocyclyl, heteroaryl, aryloxy, each of which may be substituted or unsubstituted. Preferably�,
aryl Deputy, when R6 is a phenyl which may be substituted or unsubstituted. When R6 has the meanings as defined in this paragraph, the compound of the formula II preferably represents imidazole (i.e. X is CH or C-R6, Y means N, and Z means CH or C-R8) or 1,2,3-triazole (i.e. X is CH or C-R6, Y means N, and Z N means). More preferably, the compound has formula IIa.

Alternatively, R6 preferably represents H, halogen or aryl, more preferably N. When R6 has the meanings as defined in this paragraph, the compound of the formula II preferably represents pyrazole (i.e. X is CH or C-R6, Y means CH or C-R7, and Z means N).

In one of the embodiments of the invention, when Y indicates C-R7, R7 is selected from aryl or heteroaryl, each of which may be substituted or unsubstituted. Preferably, the aryl or heteroaryl are monocyclic. Preferably, the aryl or heteroaryl substituted by one or more Halogens. In a preferred embodiment of the invention, R7 is a substituted or unsubstituted aryl. When R7 has the meaning defined in this paragraph, the compound of the formula II preferably represents pyrazole (i.e. X is CH or C-R6, Y means CH or C-R7, and Z means N) or 1,2,4-triazole (i.e., X is N, Y OZNA�AET CH or C-R7,
and Z means N).

In one of the embodiments of the invention, when Y indicates C-R7, R7 means H.

In another embodiment, when Z indicates C-R8, R8 is selected from H and aryl. Preferably, R8 is selected from H and phenyl. More preferably, R8 means H.

In one of the embodiments of the invention, R6 is a group selected from aryl, heteroaryl, heterocyclyl, S3-10-cycloalkyl where R6 group substituted by a group selected from C1-6-alkoxy, C1-6-alkoxy-C1-6-alkyl and C0-6-alkyl-CO-C0-6-alkyl, where C1-6-alkoxy, C1-6-alkoxy-C1-6-alkyl or C0-6-alkyl-CO-C0-6-alkyl substituted by a group selected from aryl, heteroaryl, heterocyclyl and C3-10-cycloalkyl. Preferably, R6 is a group selected from aryl, heteroaryl, heterocyclyl, S3-10-cycloalkyl where R6 group substituted by a group selected from C1-6-alkoxy and C1-6-alkoxy-C1-6-alkyl, where the group C1-6-alkoxy or C1-6-alkoxy-C1-6-alkyl substituted by a group selected from aryl, heteroaryl, heterocyclyl and C3-10-cycloalkyl. Preferably, R6 is a group selected from aryl, heteroaryl, heterocyclyl, S3-10-cycloalkyl where R6 group substituted by a group selected from C1-6-alkoxy and C1-6
1-6-alkyl, where the group C1-6-alkoxy or C1-6-alkoxy-C1-6-alkyl substituted by heterocyclyl. More preferably, R6 represents aryl, substituted C1-6-alkoxy, where C1-6-alkoxy substituted by heterocyclyl.

Preferably, R6 means aryl. Preferably, R6 is monocyclic ring structure, such as monocyclic aryl. In one of the embodiments of the invention, R6 is a six-membered ring structure such as phenyl.

Preferably, Deputy group C1-6-alkoxy or C1-6-alkoxy-C1-6-alkyl is monocyclic. Preferably, Deputy group C1-6-alkoxy or C1-6-alkoxy-C1-6-alkyl is six-membered. Preferably, Deputy group C1-6-alkoxy or C1-6-alkoxy-C1-6-alkyl represents heterocyclyl. Preferably, heterocyclyl is fully saturated. Preferably, heterocyclyl contains one or two heteroatom, such as nitrogen and oxygen. Preferably, heterocyclyl contains at least one heteroatom of nitrogen. In one of the embodiments of the invention, heterocyclyl is piperidinyl, PIP�retinyl or tetrahydropyranyl.
In this embodiment of the invention, the compound preferably has the formula IIa.

In one of the embodiments of the invention, when W stands for N, CONR1R2 group may be attached instead of W. In this embodiment of the invention, the compound has formula I, above.

Formula I and Ia

In compounds having formula I and, in particular, compounds having formula Ia, ring A preferably represents a substituted or unsubstituted aryl or heteroaryl component. More preferably, ring A preferably represents a substituted or unsubstituted monocyclic aryl or heteroaryl component. Even more preferably, ring A is a substituted or unsubstituted six-membered aryl or heteroaryl component. Most preferably, ring A is a substituted or unsubstituted monocyclic aryl, such as benzo component.

When the ring A is substituted, the Deputy may represent one or more groups selected from halogen, HE, C1-4-alkyl, C1-4-alkoxy, SH, NH2, NO2, CN, COOH, CONH2, CONHOH, benzoxazolinone, SO3H, SO2NH2, aryl, heteroaryl, heterocyclyl, and C3-8-cycloalkyl. When the Deputy is a C1-4-al�Il,
aryl, heteroaryl, heterocyclyl or C3-8-cycloalkyl, each of these components can be optionally substituted by one or more groups selected from halogen, HE, SH, NH2, NO2, CN, COOH, CONH2, SO3H, SO2NH2, C1-3-alkyl, C1-3-alkoxy and benzyl.

Preferably, Deputy of the A ring represents one or more groups selected from halogen, HE, C1-3-alkyl, C1-3-alkoxy, NH2, NO2, CN, COOH, CONH2, monocyclic aryl, monocyclic of heteroaryl, monocyclic heterocyclyl, and C5-8-cycloalkyl. When the Deputy is a C1-3-alkyl, monocyclic aryl, a monocyclic heteroaryl, monocyclic heterocyclyl or C5-8-cycloalkyl, each of these components can be optionally substituted by one or more groups selected from halogen, CN, COOH, CONH2and C1-3-alkoxy.

More preferably, Deputy of the A ring represents one or more groups selected from halogen, HE, C1-2-alkyl, C1-2-alkoxy and phenyl. When the Deputy is a C1-2-alkyl or phenyl, each of these components can be optionally substituted by one or more groups selected from halogen, CN, COOH, CONH2and C1-3-alkoxy.

In a preferred Varian�e compounds
having the formula I and in particular compounds having formula Ia, R1 and R2 together with N to which they are attached, form a heterocyclic group which may be substituted or unsubstituted. Preferably, heterocyclyl represents a 5 - or 6-membered monocyclic ring, and more preferably, 6-membered monocyclic ring. In some embodiments, the specified heterocyclyl contains one or two, preferably 1 additional heteroatom (i.e., in addition to N). These additional heteroatoms can be, for example, N, O and/or S. In one embodiment, heterocyclyl represents morpholino. Alternatively, heterocyclyl represents piperazinyl. In other embodiments, the specified heterocyclyl does not contain additional heteroatoms (i.e., it contains one N atom). In one embodiment, heterocyclyl is piperidinyl. When heterocyclyl is substituted, it is preferably substituted by aryl or aryl-C1-4-alkyl, where the aryl is preferably monocyclic and more preferably, phenyl. Alkyl preferably is linear. More preferably, heterocyclyl substituted aryl or aryl-C1-2-alkyl, where the aryl is preferably monocyclic and more preferred�a valid,
the phenyl.

In a preferred embodiment of compounds having formula I and, in particular, compounds having formula Ia, R1 is selected N and C1-4-alkyl, and R2 is selected from aryl, heteroaryl, heterocyclyl, S3-10-cycloalkyl, aryl-C1-6-alkyl, heteroaryl-C1-6-alkyl, heterocyclyl-C1-6-alkyl and C3-10-cycloalkyl-C1-6-alkyl, each of which may be substituted or unsubstituted. In one embodiment, R1 is selected from H, methyl and ethyl, and R2 is selected from aryl, heteroaryl, heterocyclyl and C5-8-cycloalkyl, all of which are monocyclic and may be substituted or unsubstituted. More preferably, R1 is selected from H and methyl. In one embodiment, R1 means methyl. In an alternative embodiment, R1 means H. More preferably, R2 is selected from saturated heterocyclyl and C5-8-cycloalkyl, all of which are monocyclic and may be substituted or unsubstituted. When R2 is a monocyclic C5-8-cycloalkyl, it is preferably unsubstituted. Preferably, R2 represents cyclopentyl or cyclohexyl. More preferably, R2 represents cyclohexyl, such as unsubstituted cyclohexyl. When R2 means a monocyclic saturated heterocyclyl, heterocyclic ring, preferably, contains one heteroa�ohms.
More preferably, heterocyclyl is six-membered, such as piperidinyl or tetrahydropyranyl. The nitrogen heteroatom may be substituted or unsubstituted.

In alternative implementation, R1 is selected from H, methyl and ethyl, and R2 is selected from aryl-C1-6-alkyl, heteroaryl-C1-6-alkyl, heterocyclyl-C1-6-alkyl and C5-8-cycloalkyl-C1-6-alkyl, each of which is monocyclic and may be substituted or unsubstituted. More preferably, R2 represents an aryl-C1-6-alkyl in which the aryl is monocyclic and may be substituted or unsubstituted. Even more preferably, R2 represents an aryl-C1-6-alkyl in which the aryl is monocyclic and may be substituted or unsubstituted and C1-6-alkyl is linear. Even more preferably, R2 is a phenyl-C1-6-alkyl which may be substituted or unsubstituted and C1-6-alkyl is linear. In one embodiment phenyl is unsubstituted.

In alternative implementation, R1 is selected from H, methyl and ethyl, and R2 is a C1-4-alkyl substituted by a group selected from aryl-C1-4-alkoxy, heteroaryl-C1-4-alkoxy, heterocyclyl-C1-4-alkoxy and C5-8-cycloalkyl-C1-4-alkoxy, each of which is�tsya monocyclic and may be substituted or unsubstituted.
Preferably, R2 is a substituted C1-3-alkyl. In one of the embodiments, R2 is a substituted C1-2-alkyl. Preferably, Deputy at R2 represents an aryl-C1-4-alkoxy, wherein the aryl, the aryl is monocyclic and may be substituted or unsubstituted. Even more preferably, Deputy at R2 represents an aryl-C1-4-alkoxy in which aryl is monocyclic and may be substituted or unsubstituted and C1-4-alkoxy is linear. Even more preferably, Deputy at R2 represents a phenyl-C1-4-alkoxy which can be substituted or unsubstituted, and C1-4-alkoxy is linear. In some embodiments, the phenyl is unsubstituted.

In yet another embodiment, compounds having formula I and, in particular, compounds having formula Ia, R1 is selected N and C1-4-alkyl, and R2 is selected from heterocyclyl, which may be substituted or unsubstituted. Preferably, R1 represents H, methyl or ethyl, and R2 is a bicyclic heterocyclyl, which may be substituted or unsubstituted. More preferably, R1 represents H or methyl, and R2 is a bicyclic heterocyclyl, which may be substituted or unsubstituted, where one of the rings heterocyclyl ODS�rgit two atoms of oxygen.
In one embodiment R2 represents a 3,3-dimethyl-1,5-dioxaspiro[5.5]undec-9-yl.

In an alternative preferred embodiment of compounds having formula I and, in particular, compounds having formula Ia, R1 is selected N and C1-4-alkyl, and R2 represents C2-20-alkyl. More preferably, R1 represents H, methyl or ethyl, and still more preferably, R1 represents H or methyl. Preferably, R2 is a C3-16-alkyl, where alkyl is a linear alkyl. More preferably, R2 is a C4-14-alkyl, where alkyl is a linear alkyl.

Formula IIa

In a preferred embodiment of compounds having formula IIa, R1 is selected from H and C1-4alkyl, and R2 is selected from aryl, heteroaryl, heterocyclyl, S3-10-cycloalkyl, aryl-C1-6-alkyl, heteroaryl-C1-6-alkyl, heterocyclyl-C1-6-alkyl and C3-10-cycloalkyl-C1-6-alkyl, each of which may be substituted or unsubstituted. More preferably, R1 is selected from H, methyl and ethyl, and R2 is selected from aryl, heteroaryl, heterocyclyl and C3-10-cycloalkyl, each of which may be substituted or unsubstituted. More preferably, R1 is methyl. More preferably, R2 is selected from aryl, heteroaryl, heterocyclyl and C5-8-cycloalkyl, each of which is a m�is monocyclic and may be substituted or unsubstituted.
Even more preferably, R2 is selected from aryl, such as phenyl, saturated heterocyclyl, and C5-8-cycloalkyl, all of which are monocyclic and may be substituted or unsubstituted. When R2 is a monocyclic C5-8-cycloalkyl (i.e. cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl) or aryl, preferably it is unsubstituted. Preferably, R2 represents cyclohexyl, such as unsubstituted cyclohexyl. When R2 means a monocyclic saturated heterocyclyl, heterocyclic ring, preferably contains one hetero-atom such as nitrogen atom or oxygen. More preferably, heterocyclyl is six-membered, such as piperidinyl or tetrahydropyranyl. In one of the embodiments, the heteroatom is a nitrogen atom which may be substituted or unsubstituted. Preferably, the hetero-atom in said heterocyclic group is in position 4 relative to the position of the accession of heterocyclic groups R2 to the urea nitrogen. In one of the embodiments, the nitrogen atom is substituted with monocyclic aryl is preferably phenyl)-C1-3-alkyl; preferably, a nitrogen atom substituted by a benzyl or phenylethyl; and, more preferably, a nitrogen atom substituted by benzyl.

In alternative pre�Occitania embodiment, compounds,
having a formula IIa, R1 and R2 together with N to which they are attached, form a heterocyclic group which may be substituted or unsubstituted. Preferably, heterocyclyl represents a 5 - or 6-membered monocyclic ring, and more preferably, 5-membered monocyclic ring. In some embodiments, the specified heterocyclyl contains one or two, preferably 1 additional heteroatom (i.e., in addition to N). These additional heteroatoms can be, for example, N, O and/or S. Preferably, heterocyclyl is oxazolidinyl. Preferably, the oxygen atom in oxazolidinyl is in position 3 relative to the nitrogen of urea. Preferably, oxazolidinyl substituted one, two or three methyl or ethyl groups. More preferably, oxazolidinyl substituted by two methyl or ethyl groups. Even more preferably, oxazolidinyl substituted with two methyl groups at the same carbon atom. More preferably, oxazolidinyl represents a 4,4-dimethyloxazolidine-3-yl.

In yet another preferred embodiment of compounds having formula IIa, R1 and R2 together with N to which they are attached, form a heterocyclic group which may be substituted or unsubstituted. Preferably, heterotic�sludge is a 5 - or 6-membered monocyclic ring,
and more preferably, 6-membered monocyclic ring. In some embodiments, the specified heterocyclyl contains one or two, preferably 1 additional heteroatom (i.e., in addition to N). These additional heteroatoms can be, for example, N, O and/or S. In one embodiment, heterocyclyl represents morpholino. Alternatively, heterocyclyl represents piperazinyl. In other embodiments, the specified heterocyclyl does not contain additional heteroatoms (i.e., it contains one N atom). In one embodiment, heterocyclyl is piperidinyl. When heterocyclyl is substituted, it is preferably substituted by aryl, aryl-C1-4-alkyl, C5-6-cycloalkyl or C5-6-pilooski-C1-4-alkyl, where the aryl is preferably monocyclic and more preferably, phenyl, and cycloalkyl preferably represents cyclohexyl. Alkyl preferably is linear. In one embodiment, heterocyclyl substituted aryl or aryl-C1-4-alkyl (preferably C1-2-alkyl), where aryl is preferably monocyclic and more preferably, phenyl. Aryl may be optionally substituted by one or more halogen atoms.

In the compounds having the formula, R6 is preferably selected from aryl, heteroaryl, heterocyclyl and C3-8-cycloalkyl, each of which may be substituted or unsubstituted. More preferably, R6 is selected from aryl and heteroaryl, each of which may be substituted or unsubstituted. In one of the embodiments, heteroaryl contains one heteroatom, e.g., oxygen atom or nitrogen. Preferably, the aryl or heteroaryl are monocyclic. More preferably, the aryl or heteroaryl represents a six-membered monocyclic ring, such as phenyl or pyridyl. In one of the embodiments, heteroaryl contains a nitrogen atom which is substituted by an oxygen atom, such as oxidability. In another embodiment of the implementation, R6 represents an unsubstituted monocyclic aryl, such as phenyl, or monocyclic aryl, such as phenyl, substituted by one or more groups selected from halogen, C1-2-alkoxy (optionally substituted by one or more halogen atoms) or HE.

In one embodiment, the implementation �of subramania,
R6 represents an unsubstituted or substituted 2-oxo-2,3-dihydro-1H-benzo[d]imidazole.

When R6 is substituted, Deputy preferably represents one or more groups selected from halogen, C1-4-Alcoi, aryl, heteroaryl, heterocyclyl, HE, CN, CONH2NH2, heterocyclyl-C1-4-alkoxy, aryl-C1-4-alkoxy, heteroaryl-C1-4-alkoxy, NO2, SO2NH2, SO3, C(NOH)NH2, CONHOH, 2H-tetrazol-5-yl, dimethylamino, benzylamino, methylsulfonyl, morpholinomethyl and piperidinylcarbonyl. Piperidinylcarbonyl may be optionally substituted, animetake (preferably benzoxa) or HE. Preferably, the aryl, heteroaryl or heterocyclyl are monocyclic. In one of the embodiments, aryl, heteroaryl and heterocyclyl represent a six-membered monocyclic ring. In a particular embodiment in which R6 is a monocyclic aryl, it may not necessarily be substituted by one or more groups selected from halogen, HE, C1-3-alkoxy (preferably C1-2-alkoxy), aryl (e.g. monocyclic aryl such as phenyl), heteroaryl (e.g., monocyclic of heteroaryl containing one or two nitrogen atom, or one oxygen atom), heterocyclyl-(e.g., piperazinyl, piperidinyl ulimorelin)-C
1-3-alkoxy (preferably C1-2-alkoxy), aryl(e.g. monocyclic aryl such as phenyl)-C1-3-alkoxy (preferably C1-2-alkoxy), CONH2NH2, NO2, OCHF2, SO2NH2, morpholinomethyl and C(NOH)NH2.

In another variant implementation, in which R6 is a monocyclic aryl, it may not necessarily be substituted by one or more groups selected from halogen, HE, methoxy, phenyl, pyridyl, pyrazinyl, pyridyl, pyranyl, piperazinylmethyl, piperidinylmethyl morpholinoethoxy, benzyloxy, CONH2NH2, NO2, OCHF2, SO2NH2, morpholinomethyl and C(NOH)NH2.

In one embodiment, the implementation in which R6 is a monocyclic aryl, such as phenyl, Deputy when R6 is an aryl, preferably monocyclic aryl, such as phenyl which can be substituted or unsubstituted. When he is substituted, preferably it is substituted with CONH2.

When the Deputy when R6 represents C1-4-alkoxy, aryl, heteroaryl, heterocyclyl, heterocyclyl-C1-4-alkoxy, aryl-C1-4-alkoxy, heteroaryl-C1-4-alkoxy or SO3each of these components can optionally be substituted by one or more groups selected from halogen, HE, C1-3-�laksi (which may be substituted by one or more Halogens),
CONH2, CN, NCH3CH3, NHCOCH3, methylhydroxylamine and methylhydroxylamine.

In one embodiment, compounds having the formula, R1 is selected from H and C1-4of alkyl,

R2 is selected from aryl, heteroaryl, heterocyclyl, S3-10-cycloalkyl, aryl-C1-6-alkyl, heteroaryl-C1-6-alkyl, heterocyclyl-C1-6-alkyl and C3-10-cycloalkyl-C1-6-alkyl, each of which may be optionally substituted by one or more groups selected from R2a, halogen, HE, OR2a, OCOR2a, SH, SR2a, SCOR2a, NH2, NHR2a, NHSO2NH2, NHSO2R2a, NR2aCOR2b, NHC(NH)NH2, NHCOR2a, NR2aR2b, COR2a, CSR2a, CN, COOH, COOR2a, CONH2, CONHOH, CONHR2a, CONHOR2a, C(NOH)NH2, SO2R2a, SO3H, SO2NH2, CONR2aR2b, SO2NR2aR2b, where R2a and R2b are independently selected from C1-6of alkyl, substituted C1-6of alkyl, aryl, heteroaryl, S3-8-cycloalkyl and heterocyclyl, or R2a and R2b, together with the heteroatom to the cat�rum they are attached,
can form heterocyclyl,

where, when Deputy when R2 represents C1-6-alkyl, substituted C1-6-alkyl, aryl, heteroaryl, S3-8-cycloalkyl, heterocyclyl or a group containing one or more of these components, each of these components can be optionally substituted by one or more groups selected from R2c, halogen, HE, OR2c, OCOR2c, SH, SR2c, SCOR2c, NH2, NHR2c, NHSO2NH2, NHSO2R2c, NR2cCOR2d, NHC(NH)NH2, NHCOR2c, NR2cR2d, COR2c, CSR2c, CN, COOH, COOR2c, CONH2, CONHOH, CONHR2c, CONHOR2c, C(NOH)NH2, SO2R2c, - SO3H, SO2NH2, CONR2cR2d, SO2NR2cR2d, where R2c and R2d are independently selected from C1-6of alkyl, substituted C1-6of alkyl, aryl, heteroaryl, S3-8-cycloalkyl and heterocyclyl, or R2c and R2d, together with the heteroatom to which they are attached, can form heterocyclyl,

R6 is selected from aryl, GE�of erorile,
heterocyclyl, S3-10-cycloalkyl, each of which may be optionally substituted by one or more groups selected from R6a, halogen, HE, OR6a, OCOR6a, SH, SR6a, SCOR6a, NH2, NHR6a, NHSO2NH2, NHSO2R6a, NR6aCOR6b, NHC(NH)NH2, NHCOR6a, NR6aR6b, COR6a, CSR6a, CN, COOH, COOR6a, CONH2, CONHOH, CONHR6a, CONHOR6a, C(NOH)NH2, SO2R6a, SO3H, SO2NH2, CONR6aR6b, SO2NR6aR6b, where R6a and R6b are independently selected from C1-6of alkyl, substituted C1-6of alkyl, aryl, heteroaryl, S3-8-cycloalkyl and heterocyclyl, or R6a and R6b, together with the heteroatom to which they are attached, can form heterocyclyl, and where, when R6 represents heteroaryl or heterocyclyl, each of these components can be optionally substituted by one or more oxygen atoms,

where, when Deputy when R6 represents C1-6-alkyl, substituted C1-6-alkyl, aryl, heteroaryl, S3-8-cycloalkyl, heterocyclyl or a group containing one or more of these components, each of these components can be optionally substituted by one or more groups selected from R6c, halogen, HE, OR6c, OCOR6c, SH, SR6c, SCOR6c, NH2, NHR6c, NHSO2NH2, NHSO2R6c, NR6cCOR6d, NHC(NH)NH2, NHCOR6c, NR6cR6d, COR6c, CSR6c, CN, COOH, COOR6c, CONH2, CONHOH, CONHR6c, CONHOR6c, C(NOH)NH2, SO2R6c, SO3H, SO2NH2, CONR6cR6d, SO2NR6cR6d where R6c and R6d independent� selected from C
1-6of alkyl, substituted C1-6of alkyl, aryl, heteroaryl, S3-8-cycloalkyl and heterocyclyl, or R6c and R6d, together with the heteroatom to which they are attached, can form heterocyclyl, and where, when the Deputy when R6 represents heteroaryl or heterocyclyl, each of these components can be optionally substituted by one or more oxygen atoms, and

In the above embodiments, preferably, R1 is selected from H, methyl and ethyl, and R2 is selected from aryl, heteroaryl, heterocyclyl and C3-10cycloalkyl, each of which may be substituted or unsubstituted. More preferably, R1 is methyl. More preferably, R2 is selected from aryl, heteroaryl, heterocyclyl and C3-10-cycloalkyl, all of which are monocyclic and may be substituted or unsubstituted.Even more preferably,
R2 is selected from heterocyclyl and C3-10-cycloalkyl, all of which are monocyclic and may be substituted or unsubstituted. Preferably, heterocyclyl is fully saturated. When R2 is a monocyclic C5-8-cycloalkyl (i.e. cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl), preferably it is unsubstituted. In one of the embodiments, R2 is cyclopentyl or cyclohexyl, such as the unsubstituted cyclopentyl or unsubstituted cyclohexyl. When R2 means a monocyclic saturated heterocyclyl, heterocyclic ring, preferably contains one hetero-atom such as nitrogen atom or oxygen. Preferably, heterocyclyl is six-membered, such as piperidinyl or tetrahydropyranyl. Preferably, the hetero-atom in said heterocyclic group is in position 4 relative to the position of the accession of heterocyclic groups R2 to the urea nitrogen. In one of the embodiments, the heteroatom is a nitrogen heteroatom which can be substituted or unsubstituted.

In one of the embodiments, a nitrogen atom substituted by a group of monocyclic aryl(preferably phenyl)-C1-3-alkyl; preferably, a nitrogen atom substituted by a benzyl or phenylethyl; and, more preferably, a nitrogen atom substituted by benzyl.

In one of the embodiments R5 represents H, halogen, HE, or C1-4-alkyl. Preferably, R5 represents N.

In another embodiment of the implementation, R6 is selected from aryl, heteroaryl and heterocyclyl, each of which may be substituted or unsubstituted. Preferably, R6 is selected from monocyclic aryl (such as phenyl), monocyclic of heteroaryl (such as pyridyl), and heterocyclyl, each of which may be substituted or unsubstituted. In one of the embodiments, R6 is an unsubstituted aryl. When R6 is a substituted Ari�,
preferably it is substituted with one or more groups selected from halogen, R6a, HE, OR6a, NH2, NO2, NHC(NH)NH2, NHR6a, NR6aR6b, C(NOH)NH2, COR6a, COOH, COOR6a, CONH2, CONHOH, SO2R6a, SO2NR6aR6b, where R6a and R6b are independently selected from C1-6of alkyl, substituted C1-6of alkyl, aryl, heteroaryl, S3-8-cycloalkyl and heterocyclyl,

where, when Deputy when R6 represents C1-6-alkyl, substituted C1-6-alkyl, aryl, heteroaryl, S3-8-cycloalkyl, heterocyclyl or is a group containing one or more of these components, each of these components can be optionally substituted by one or more groups selected from OR6c, and HE CONH2where R6c and R6d are independently selected from C1-6of alkyl, substituted C1-6of alkyl, aryl, heteroaryl, S3-8-cycloalkyl and heterocyclyl, and where, when the Deputy when R6 represents heteroaryl or heterocyclyl, each of these components can be optionally substituted by one or more oxygen atoms.

Preferably, when R6 is a substituted aryl, it is substituted with one or more groups selected from halogen, HE, C1-4-alkoxy, CONH2, C(NOH)NH2, CONHOH, SO2-C1-4-alkyl, heterocyclyl (optionally substituted by oxygen atom), aryl (optionally substituted CONH2
). In one of the embodiments of the invention, R6 may be substituted by one or more groups selected from 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl, 3-carbamoylphenoxy, 2H-tetrazol-5-yl, C1-4-alkoxy, halogen, HE, CONHOH.

When R6 represents heterocyclyl, preferably it is substituted by an atom of oxygen. Deputy R6 may represent a 2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-ilili-oxo-2,3-dihydrobenzo[d]oxazol-5-yl.

When R6 represents heteroaryl, preferably it is unsubstituted or substituted by oxygen atom. For example, heterocyclyl may contain N-oxide. In one of the embodiments of the invention, R6 represents a pyridyl or pyridyl oxide.

In a preferred embodiment of compounds having formula IIb, R1 is selected from H and C1-4-alkyl, and R2 is selected from aryl, heteroaryl, heterocyclyl, S3-10-cycloalkyl, aryl-C1-6-alkyl, heteroaryl-C1-6-alkyl, heterocyclyl-C1-6-alkyl and C3-10-cycloalkyl-C1-6-alkyl, each of which may be substituted or unsubstituted. More preferably, R1 is selected from H, methyl and ethyl, and R2 is selected from aryl, heteroaryl, heterocyclyl and
3-10-cycloalkyl, each of which may be substituted or unsubstituted. More preferably, R1 is methyl. More preferably, R2 is selected from aryl, heteroaryl, heterocyclyl and C5-8-cycloalkyl, all of which are monocyclic and may be substituted or unsubstituted. Even more preferably, R2 is selected from monocyclic aryl, such as phenyl and may be substituted or unsubstituted. When R2 is substituted, the Deputy may represent aryl, C1-4-alkoxy, aryl-C1-4-alkoxy or aryloxy. Preferably, the under when R2 represents aryl, C1-3-alkoxy, aryl-C1-3-alkoxy or aryloxy, where aryl is monocyclic and more preferably, phenyl.

When R2 is a monocyclic C5-8-cycloalkyl or aryl, preferably it is unsubstituted. Preferably, R2 represents cyclohexyl, such as unsubstituted cyclohexyl. When R2 means a monocyclic saturated heterocyclyl, heterocyclic ring, preferably contains one hetero-atom such as nitrogen atom or oxygen. More preferably, heterocyclyl is six-membered, such as piperidinyl or tetrahydropyranyl. In one of the embodiments, the heteroatom is gateroad�m nitrogen,
which may be substituted or unsubstituted. Preferably, the hetero-atom in said heterocyclic group is in position 4 relative to the position of the accession of heterocyclic groups R2 to the urea nitrogen. In one of the embodiments, a nitrogen atom substituted by a group of monocyclic aryl is preferably phenyl)-C1-3-alkyl.

In an alternative preferred embodiment of compounds having formula IIb, R1 and R2 together with N to which they are attached, form a heterocyclic group which may be substituted or unsubstituted. Preferably, heterocyclyl represents a 5 - or 6-membered monocyclic ring, and more preferably, 5-membered monocyclic ring. In some embodiments, the specified heterocyclyl contains one or two, preferably 1 additional heteroatom (i.e., in addition to N). These additional heteroatoms can be, for example, N, O and/or S. Preferably, heterocyclyl is oxazolidinyl. Preferably, the oxygen atom in oxazolidinyl is in position 3 relative to the nitrogen of urea. Preferably, oxazolidinyl substituted one, two or three methyl or ethyl groups. More preferably, oxazolidinyl substituted by two methyl or ethyl groups. Even more preferred�Stateline,
oxazolidinyl substituted with two methyl groups at the same carbon atom. More preferably, oxazolidinyl represents a 4,4-dimethyloxazolidine-3-yl.

In yet another preferred embodiment of compounds having formula IIb, R1 and R2 together with N to which they are attached, form a heterocyclic group which may be substituted or unsubstituted. Preferably, heterocyclyl represents a 5 - or 6-membered monocyclic ring, and more preferably, 6-membered monocyclic ring. In some embodiments, the specified heterocyclyl contains one or two, preferably 1 additional heteroatom (i.e., in addition to N). This additional heteroatoms can be, for example, N, O and/or S. In one embodiment, heterocyclyl represents morpholino. Alternatively, heterocyclyl represents piperazinyl. In other embodiments, the specified heterocyclyl does not contain additional heteroatoms (i.e., it contains one N atom). In one embodiment, heterocyclyl is piperidinyl. When heterocyclyl is substituted, it is preferably substituted by aryl, aryl-C1-4-alkyl, C5-6-cycloalkyl or C5-6-cycloalkyl-C1-4-alkyl, where aryl preferably is monocyclic�skim,
and more preferably, phenyl, and cycloalkyl preferably represents cyclohexyl. Alkyl preferably is linear. In one embodiment, heterocyclyl substituted aryl or aryl-C1-4-alkyl (preferably C1-2-alkyl), where aryl is preferably monocyclic and more preferably, phenyl. Aryl may be optionally substituted by one or more halogen atoms.

In compounds having formula IIb, R7 is preferably selected aryl, heteroaryl, heterocyclyl and C3-8-cycloalkyl, each of which may be substituted or unsubstituted. More preferably, R7 SEL�from an aryl or heteroaryl,
each of which may be substituted or unsubstituted. In one of the embodiments of heteroaryl contains one heteroatom, e.g., oxygen atom or nitrogen. Preferably, the aryl or heteroaryl are monocyclic. More preferably, the aryl or heteroaryl represents a six-membered monocyclic ring. In one of the embodiments, heteroaryl contains a nitrogen atom which is substituted by an oxygen atom, such as oxidability. In another embodiment of the implementation, R7 represents an unsubstituted monocyclic aryl, such as phenyl, or monocyclic aryl, such as phenyl, substituted by one or more groups selected from halogen, C1-2-alkoxy (optionally substituted by one or more halogen atoms) or HE. In a particular embodiment of the invention, R7 represents an unsubstituted monocyclic aryl, such as phenyl.

When R7 is substituted, Deputy preferably represents one or more groups selected from halogen, C1-4-Alcoi, aryl, heteroaryl, heterocyclyl, HE, CONH2NH2, heterocyclyl-C1-4-alkoxy, aryl-C1-4-alkoxy, heteroaryl-C1-4-alkoxy, NO2, SO2NH2, SO3, C(NOH)NH2and morpholinomethyl. Preferably, the aryl, heteroaryl and heterocyclyl are mono�ilycheskie.
In one of the embodiments, aryl, heteroaryl and heterocyclyl represent a six-membered monocyclic ring. In a particular embodiment in which R7 represents a monocyclic aryl, it may not necessarily be substituted by aryl or heteroaryl, each of which is monocyclic.

Formula IIc

In a preferred embodiment of compounds having formula IIc, R1 is selected from H and C1-4-alkyl, and R2 is selected from aryl, heteroaryl, heterocyclyl, S3-10-cycloalkyl, aryl-C1-6-alkyl, heteroaryl-C1-6-alkyl, heterocyclyl-C1-6-alkyl and C3-10-cycloalkyl-C1-6-alkyl, each of which may be substituted or unsubstituted. More preferably, R1 is selected from H, methyl and ethyl, and R2 is selected from aryl, heteroaryl, heterocyclyl and C3-10-cycloalkyl, each of which may be substituted or unsubstituted. More preferably, R1 is methyl. More preferably, R2 is selected from aryl, heteroaryl, heterocyclyl and C5-8-picoalgae, all of which are monocyclic and may be substituted or unsubstituted. Even more preferably, R2 is selected from aryl, such as phenyl, saturated heterocyclyl, and C5-8-cycloalkyl, all of which are monocyclic and may be substituted or unsubstituted. When 2 is a monocyclic C
3-8-cycloalkyl or aryl, preferably it is unsubstituted. Preferably, R2 represents cyclohexyl, such as unsubstituted cyclohexyl. When R2 means a monocyclic saturated heterocyclyl, heterocyclic ring, preferably contains one heteroatom, such as nitrogen or oxygen. More preferably, heterocyclyl is six-membered, such as piperidinyl or tetrahydropyranyl. In one of the embodiments, the heteroatom is a nitrogen atom which may be substituted or unsubstituted. Preferably, the hetero-atom in said heterocyclic group is in position 4 relative to the position of the accession of heterocyclic groups R2 to the urea nitrogen. In one of the embodiments, a nitrogen atom substituted by a group of monocyclic aryl-(predpochtitelno)-C1-3-alkyl.

In an alternative preferred embodiment of compounds having formula IIc, R1 and R2 together with N to which they are attached, form a heterocyclic group which may be substituted or unsubstituted. Preferably, heterocyclyl represents a 5 - or 6-membered monocyclic ring, and more preferably, 5-membered monocyclic ring. In some embodiments, the specified heterocyclyl contains one or two of predpochtitel�but 1,
additional heteroatom (i.e., in addition to N). These additional heteroatoms can be, for example, N, O and/or S. Preferably, heterocyclyl is oxazolidinyl. Preferably, the oxygen atom in oxazolidinyl is in position 3 relative to the nitrogen of urea. Preferably, oxazolidinyl substituted one, two or three methyl or ethyl groups. More preferably, oxazolidinyl substituted by two methyl or ethyl groups. Even more preferably, oxazolidinyl substituted with two methyl groups at the same carbon atom. More preferably, oxazolidinyl represents a 4,4-dimethyloxazolidine-3-yl.

In yet another preferred embodiment of compounds having formula IIc, R1 and R2 together with N to which they are attached, form a heterocyclic group which may be substituted or unsubstituted. Preferably, heterocyclyl represents a 5 - or 6-membered monocyclic ring, and more preferably, 6-membered monocyclic ring. In some embodiments, the specified heterocyclyl contains one or two, preferably 1 additional heteroatom (i.e., in addition to N). These additional heteroatoms can be, for example, N, O and/or S. In one embodiment, heterocyclyl ameri� a morpholino.
Alternatively, heterocyclyl represents piperazinyl. In other embodiments, the specified heterocyclyl does not contain additional heteroatoms (i.e., it contains one N atom). In one embodiment, heterocyclyl is piperidinyl. When heterocyclyl is substituted, it is preferably substituted by aryl, aryl-C1-4-alkyl, C5-6-cycloalkyl or C5-6-cycloalkyl-C1-4-alkyl, where the aryl is preferably monocyclic and more preferably, phenyl, and cycloalkyl preferably represents cyclohexyl. Alkyl preferably is linear. In one embodiment, heterocyclyl substituted aryl or aryl-C1-4-alkyl (preferably C1-2-alkyl), where aryl is preferably monocyclic and more preferably, phenyl. Aryl may be optionally substituted by one or more Halogens.

Even more preferably, R5 is selected from H and halogen, such as F, Cl and Br. In one of the embodiments, R5 is a H.

In compounds having formula IIc, R6 is preferably selected aryl, heteroaryl, hetero�Ollila and C
3-8-cycloalkyl, each of which may be substituted or unsubstituted. More preferably, R6 is selected from aryl and heteroaryl, each of which may be substituted or unsubstituted. In one of the embodiments of heteroaryl contains one heteroatom, e.g., oxygen atom or nitrogen. Preferably, the aryl or heteroaryl are monocyclic. More preferably, the aryl or heteroaryl represents a six-membered monocyclic ring. In one of the embodiments, heteroaryl contains a nitrogen atom which is substituted by an oxygen atom, such as oxidability. In another embodiment of the implementation, R6 represents an unsubstituted monocyclic aryl, such as phenyl, or monocyclic aryl, such as phenyl, substituted by one or more groups selected from halogen, C1-2-alkoxy (optionally substituted by one or more halogen atoms) or HE. In a particular embodiment of the invention, R6 represents an unsubstituted aryl, preferably monocyclic aryl, such as phenyl.

When R6 is substituted, Deputy preferably represents one or more groups selected from halogen, C1-4-Alcoi, aryl, heteroaryl, heterocyclyl, HE, CONH2NH2, heterocyclyl-C1-4-alkoxy, aryl-C1-4-alkoxy, heteroaryl�-C
1-4-alkoxy, NO2, SO2NH2, SO3, C(NOH)NH2and morpholinomethyl. Preferably, the aryl, heteroaryl or heterocyclyl are monocyclic. In one of the embodiments, aryl, heteroaryl and heterocyclyl represent a six-membered monocyclic ring. In a particular embodiment in which R6 is a monocyclic aryl, it may not necessarily be substituted by one or more groups selected from halogen, HE, C1-3-alkoxy, aryl (e.g. monocyclic aryl such as phenyl), heteroaryl (e.g., monocyclic of heteroaryl containing one or two nitrogen atom, or one oxygen atom), heterocyclyl-(e.g., piperazinyl, piperidinyl or morpholino)-C1-3-alkoxy, aryl-(e.g. monocyclic aryl such as phenyl)-C1-3-alkoxy, CONH2NH2, NO2, OCHF2, SO2NH2, morpholinomethyl and C(NOH)NH2.

In one embodiment of the implementation, when R6 is a monocyclic aryl, such as phenyl, Deputy when R6 is an aryl, preferably monocyclic aryl, such as phenyl which can be substituted or unsubstituted. When he is substituted, preferably it is substituted with CONH2.

When the Deputy when R6 represents C1-4-alkoxy, aryl, g�teroare,
heterocyclyl, heterocyclyl-C1-4-alkoxy, aryl-C1-4-alkoxy, heteroaryl-C1-4-alkoxy or SO3each of these components can optionally be substituted by one or more groups selected from halogen, HE, C1-3-alkoxy (which may be substituted by one or more Halogens), CONH2, CN, NCH3CH3, NHCOCH3, methylhydroxylamine and methylhydroxylamine.

Formula IId

In a preferred embodiment of compounds having formula IId, R1 is selected from H and C1-4-alkyl, and R2 is selected from aryl, heteroaryl, heterocyclyl, S3-10-cycloalkyl, aryl-C1-6-alkyl, heteroaryl-C1-6-alkyl, heterocyclyl-C1-6-alkyl and C3-10-cycloalkyl-C1-6-alkyl, each of which may be substituted or unsubstituted. More preferably, R1 is selected from H, methyl and ethyl, and R2 is selected from aryl, heteroaryl, heterocyclyl and C3-10-cycloalkyl, each of which may be substituted or unsubstituted. More preferably R1 is methyl. More preferably, R2 is selected from aryl, heteroaryl, heterocyclyl and C5-8-cycloalkyl, all of which are monocyclic and may be substituted or unsubstituted. Even more preferably, R2 is selected from aryl, such as phenyl, saturated heterocyclyl, and C5-8-cycloalkyl, each of Kotor�x is monocyclic and may be substituted or unsubstituted.
Even more preferably, R2 represents aryl, such as phenyl, which is monocyclic and may be substituted or unsubstituted. When R2 is substituted, Deputy preferably represents one or more Halogens.

In one of the embodiments, R2 is a cyclohexyl, such as unsubstituted cyclohexyl. When R2 means a monocyclic saturated heterocyclyl, heterocyclic ring, preferably contains one heteroatom, such as nitrogen or oxygen. More preferably, heterocyclyl is six-membered, such as piperidinyl or tetrahydropyranyl. In one of the embodiments, the heteroatom is a nitrogen atom which may be substituted or unsubstituted. Preferably, the hetero-atom in said heterocyclic group is in position 4 relative to the position of the accession of heterocyclic groups R2 to the urea nitrogen. In one of the embodiments, a nitrogen atom substituted by a group of monocyclic aryl is preferably phenyl)-C1-3-alkyl.

In an alternative preferred embodiment of compounds having formula IId, R1 and R2 together with N to which they are attached, form a heterocyclic group which may be substituted or unsubstituted. Preferably, heterocyclyl performance�em a 5 - or 6-membered monocyclic ring,
and more preferably, 5-membered monocyclic ring. In some embodiments, the specified heterocyclyl contains one or two, preferably 1 additional heteroatom (i.e., in addition to N). These additional heteroatoms can be, for example, N, O and/or S. Preferably, heterocyclyl is oxazolidinyl. Preferably, the oxygen atom in oxazolidinyl is in position 3 relative to the nitrogen of urea. Preferably, oxazolidinyl substituted one, two or three methyl or ethyl groups. More preferably, oxazolidinyl substituted by two methyl or ethyl groups. Even more preferably, oxazolidinyl substituted with two methyl groups at the same carbon atom. More preferably, oxazolidinyl represents a 4,4-dimethyloxazolidine-3-yl.

In yet another preferred embodiment of compounds having formula IId, R1 and R2 together with N to which they are attached, form a heterocyclic group which may be substituted or unsubstituted. Preferably, heterocyclyl represents a 5 - or 6-membered monocyclic ring, and more preferably, 6-membered monocyclic ring. In some embodiments, the specified heterocyclyl contains one or two, preferably 1, additional� of a heteroatom (i.e.,
in addition to N). These additional heteroatoms can be, for example, N, O and/or S. In one embodiment, heterocyclyl represents morpholino. Alternatively, heterocyclyl represents piperazinyl. In other embodiments, the specified heterocyclyl does not contain additional heteroatoms (i.e., it contains one N atom). In one embodiment, heterocyclyl is piperidinyl. When heterocyclyl is substituted, it is preferably substituted by aryl, aryl-C1-4-alkyl, C5-6-cycloalkyl or C5-6-cycloalkyl-C1-4-alkyl, where the aryl is preferably monocyclic and more preferably, phenyl, and cycloalkyl preferably represents cyclohexyl. Alkyl preferably is linear. In one embodiment, heterocyclyl substituted aryl or aryl-C1-4-alkyl (preferably C1-3-alkyl), where aryl is preferably monocyclic and more preferably, phenyl. Aryl may be optionally substituted by one or more halogen atoms.

In compounds having formula IId, R7 is preferably selected aryl, heteroaryl, heterocyclyl and C3-8-cycloalkyl, each of which may be substituted or unsubstituted. More preferably, R7 is selected from aryl and heteroaryl, each of which may be substituted or unsubstituted. In one of the embodiments of heteroaryl contains one heteroatom, e.g., oxygen atom or nitrogen. Preferably, the aryl or heteroaryl are monocyclic. More preferably, the aryl or heteroaryl represents a six-membered monocyclic ring. In one of the embodiments, heteroaryl contains a nitrogen atom which is substituted by an oxygen atom, such as oxidability. In another embodiment of the implementation, R7 represents an unsubstituted monocyclic aryl, such as phenyl, or monocyclic aryl, such as phenyl, substituted by one or more groups selected from halogen, C1-2-alkoxy (optionally substituted by one or more halogen atoms) or HE.

When R7 is substituted, Deputy preferably represents one or more groups selected from halogen, C1-4-Alcoi, aryl, heteroaryl, heterocyclyl, HE, CONH2NH2, heterocyclyl-C1-4-alkoxy, aryl-C
-alkoxy, heteroaryl-C1-4-alkoxy, NO2, SO2NH2, SO3, C(NOH)NH2and morpholinomethyl. Preferably, the aryl, heteroaryl or heterocyclyl are monocyclic. In one of the embodiments, aryl, heteroaryl and heterocyclyl represent a six-membered monocyclic ring. In a particular embodiment in which R7 represents a monocyclic aryl, it may not necessarily be substituted by one or more groups selected from halogen, HE, C1-3-alkoxy, aryl (e.g. monocyclic aryl such as phenyl), heteroaryl (e.g., monocyclic of heteroaryl containing one or two nitrogen atom, or one oxygen atom), heterocyclyl-(e.g., piperazinyl, piperidinyl or morpholino)-C1-3-alkoxy, aryl-(e.g. monocyclic aryl such as phenyl)-C1-3-alkoxy, CONH2NH2, NO2, OCHF2, SO2NH2, morpholinomethyl and C(NOH)NH2. In one of the embodiments, when R7 represents a monocyclic aryl, such as phenyl, Deputy R7 represents aryl(e.g. monocyclic aryl such as phenyl)-C1-3-alkoxy.

When the Deputy when R7 represents C1-4-alkoxy, aryl, heteroaryl, heterocyclyl, heterocyclyl-C1-4-alkoxy, aryl-C1-4-an alkoxy heteroaryl-C
1-4-alkoxy or SO3each of these components can optionally be substituted by one or more groups selected from halogen, HE, C1-3-alkoxy (which may be substituted by one or more Halogens), CONH2, CN, NCH3CH3, NHCOCH3, methylhydroxylamine and methylhydroxylamine.

In an alternative embodiment, the invention presents compounds having formula I or formula II:

provided that ring A in compounds having formula I does not form a pyridine, pyrimidine, substituted pyridine or substituted pyrimidine, when R1 and R2 together with N to which they are attached, form piperidinyl, piperazinyl, substituted piperidinyl or substituted piperazinyl,

provided that when R1 or R2 is methyl, the other of R1 or R2 does not mean 4-chlorobutyl, 4-azidomethyl or 4-isothiocyanato�scrap,
and

provided that the compound is not (4-phenyl-1H-imidazol-1-yl)(4-(quinolin-2-ylmethyl)piperazine-1-yl)methanon.

In accordance with the second aspect of the invention proposed pharmaceutical composition comprising a compound according to the first aspect of the invention together with one or more pharmaceutically acceptable excipients.

The pharmaceutical compositions of this invention include any of the compounds according to the first aspect of the present invention with any pharmaceutically acceptable carrier, auxiliary substance or excipient. Pharmaceutically acceptable carriers, excipients and fillers which can be used in pharmaceutical compositions according to the invention are conventionally used in pharmaceutical compositions, include, but are not limited to, sugars, sugar alcohols, starches, ion exchange materials, alumina, aluminum stearate, lecithin, seroprotective, such as human serum albumin, buffer substances such as phosphates, glycerine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as Protamine sulfate, disodium phosphate sodium, secondary acid potassium phosphate, sodium chloride, zinc salts, colloidal cream�rd,
magnesium trisilicate, polyvinylpyrrolidone, substances based on cellulose, polyethylene glycol, natrocarbonatite, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and lanolin (wool fat).

Pharmaceutical compositions according to this invention may be administered orally, parenterally, by inhalation irrigation, rectally, nasally, buccally, vaginally or via an implanted reservoir. Preferably oral administration. Pharmaceutical compositions according to this invention can include any suitable non-toxic pharmaceutically acceptable carriers, adjuvants or excipients. As used herein, the term parenteral includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, vnutrisustavne, epigastric, into the cavity of the spinal canal, inside the affected tissues and intracranial introduction or infusion methods.

Pharmaceutical compositions can be in the form of a sterile injectable preparation, for example, in the form of a sterile injectable aqueous or oily suspension. This suspension can be obtained by known in the art methods using suitable dispersing or wetting agents (such as, for example, tween 80) and suspendida agents. Sterile injectable� the drug may also be a sterile injectable solution or suspension in a non-toxic suitable for injecting a solvent or diluent,
for example, a solution in 1,3-butanediol. Acceptable fillers and solvents that can be used are mannitol, water, ringer's solution and isotonic sodium chloride solution. In addition, sterile fatty oils conventionally used as a solvent or suspendida environment. This purpose can be used any soft fatty oil, including synthetic mono - or diglycerides. When receiving injectable drugs are used fatty acids such as oleic acid, and their glyceride derivatives, as well as natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in polyoxyethylated form. These oil solutions or suspensions may also contain long-chain alcohol diluent or dispersant, such as described in Ph. Helv or a similar alcohol.

Pharmaceutical compositions according to this invention may be administered orally in any orally acceptable dosage form including, but not limited to, capsules, tablets, powders, granules and aqueous suspensions and solutions. These dosage forms prepared using a well-known in the art methods of preparing pharmaceutical compositions. In the case of tablets for oral use as a carrier is usually used lactose or corn KRA�small.
Also usually add a lubricant such as magnesium stearate. For oral administration in the form of capsules used diluents include lactose and corn starch. When the aqueous suspension is intended for oral administration, the active ingredient is combined with emulsifying and suspendresume agents. If desirable, can be added, certain sweetening and/or imparting odor and/or staining agents.

Pharmaceutical compositions according to this invention can also be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing the compounds of the present invention with no causing irritation excipient, which is a solid at room temperature, but liquid at rectal temperature and therefore will melt in the rectum to release the active components. Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.

Pharmaceutical compositions according to this invention may be administered using a nasal spray or by inhalation. Such compositions are obtained by means well known in the art methods of preparing pharmaceutical formulations, and they can be prepared in the form of saline, using benzyl alcohol �whether other suitable preservatives,
stimulants suction to enhance bioavailability, fluorocarbons, and/or other solvent or dispersing agents known in the art.

Compounds of the present invention may be administered in a dose of from about 1 to about 20,000 μg/kg per dose, depending on the conditions of treatment or prevention, and the characteristics of the subject, which introduces the connection. In many cases, the dose may be from about 1 to about 1500 μg/kg per dose. The dosage of the compound can be easily determined by a person skilled in the art having access to this description.

In a particular embodiment of the invention, the pharmaceutical composition according to the invention further comprises one or more additional pharmaceutically active ingredient. The connection according to the invention can be administered with one or more additional pharmaceutically active ingredients. This can be in the form of a single composition containing the compound of the invention and one or more additional pharmaceutically active ingredients. Alternatively, it might be two or more separate compositions, where the connection according to the invention is contained in one composition and one or more additional active ingredients are contained in one or more separate compositions.

In the third aspect, the present invention p�edlagaet connection according to the first aspect of the invention,
or composition according to the second aspect for use in therapy.

In a fourth aspect, the invention provides the compound according to the first aspect of the invention, or a composition according to the second aspect for use for the treatment or prevention of conditions which has manifested or symptoms associated with a substrate of the enzyme FAAH, where the following conditions are true first aspect that applies, (i) the ring A in compounds having formula I does not form a pyridine, pyrimidine, substituted pyridine or substituted pyrimidine, when R1 and R2 together with N to which they are attached, form piperidinyl, piperazinyl, substituted piperidinyl or substituted piperazinyl, (ii) when R1 or R2 means methyl, the other of R1 or R2 does not mean 4-chlorobutyl, 4-azidomethyl, or 4-izotiotsianovoy, and (iii) the compound is not (4-phenyl-1H-imidazol-1-yl)(4-(quinolin-2-ylmethyl)piperazine-1-yl)Metronom.

The invention also provides use of a compound according to the first aspect of the invention, or compositions according to the second aspect, in the manufacture of a medicament for the treatment or prevention of conditions, which manifested itself, or symptoms associated with a substrate of the enzyme FAAH, only provided that the following conditions are true first aspect that applies, (i) the ring A in compounds having formula I does not form a n�ridin,
pyrimidine, substituted pyridine or substituted pyrimidine, when R1 and R2 together with N to which they are attached, form piperidinyl, piperazinyl, substituted piperidinyl or substituted piperazinyl, (ii) when R1 or R2 means methyl, the other of R1 or R2 does not mean 4-chlorobutyl, 4-azidomethyl, or 4-izotiotsianovoy, and (iii) the compound is not (4-phenyl-1H-imidazol-1-yl)(4-(quinolin-2-ylmethyl)piperazine-1-yl)Metronom.

A number of States that have developed, or symptoms associated with a substrate of the enzyme FAAH, well known in the art. Some of them have been discussed above.

In the fifth aspect of the invention also provides a method of treating or preventing, States that have developed, or symptoms associated with a substrate of the enzyme FAAH, the method comprising administering to a subject in need of such treatment or prevention, a therapeutically effective amount of a compound according to the first aspect of the invention or the composition according to the second aspect, only provided that the following conditions are true first aspect that applies, (i) the ring A in compounds having formula I does not form a pyridine, pyrimidine, substituted pyridine or substituted pyrimidine, when R1 and R2, together with N, to which they are attached, form piperidinyl, piperazinyl, substituted piperidinyl or substituted piperazinyl, (ii) when R1 �if R2 means methyl,
the other of R1 or R2 does not mean 4-chlorobutyl, 4-azidomethyl, or 4-izotiotsianovoy, and I) compound is not (4-phenyl-1H-imidazol-1-yl)(4-(quinolin-2-ylmethyl) piperazine-1-yl)Metronom.

The connection according to the fourth aspect or the method according to the fifth aspect, where the condition is a disease associated with the endocannabinoid system.

In some embodiments, the condition to be treated, can be chosen from the following:

(ii) dizziness, vomiting, and nausea, in particular resulting from chemotherapy;

(iii) digestive disorders, in particular anorexia or cachexia of various natures;

(iv) neurological or psychiatric pathologies such as tremors, dyskinesia, dystonia, spasms, OCD, Tourette's syndrome, all forms of depression and anxiety� of any nature and origin,
mood disorders and psychoses;

In the sixth aspect of the present invention, it is proposed the use of compounds according to the first aspect of the invention in the manufacture of a medicament for the treatment or prevention of a condition which manifested itself, or symptoms associated with a substrate of the enzyme FAAH, only under the condition that occurs after�following condition to the first aspect,
used that ring A in compounds having formula I does not form a pyridine, pyrimidine, substituted pyridine or substituted pyrimidine, when R1 and R2 together with N to which they are attached, form piperidinyl, piperazinyl, substituted piperidinyl or substituted piperazinyl.

Examples of conditions relevant to the sixth aspect described above.

In some embodiments, fourth, fifth or sixth aspects also apply other restrictions on the first dimension.

The invention will now be described in detail with examples:

1. Methods of synthesis

The methods used for the synthesis of compounds according to the invention, illustrated with the aid of the following General schemes and preparative examples. All compounds and intermediate compounds were characterized by means of nuclear magnetic resonance (NMR). Starting materials and reagents used in the preparation of these compounds are available from commercial suppliers or can be obtained by methods known to the person skilled in the art. These General schemes only illustrate the methods by which the compounds of the invention can be synthesized, and various modifications to these schemes can be made and will be offered by experts in the field relevant to the given description.

Room temperature at the following �hemah means a temperature in the range from 20°C to 25°C.

BENZOTRIAZOLES

5-Bromo-1H-benzo[d][1,2,3]triazole (1H-benzo[d][1,2,3]triazole the formation of a derivative).

To a solution of 4-Brabanthal-1,2-diamine (10 g, 53.5 mmol) in a mixture of acetic acid (20 ml, 349 mmol) and water (100 ml) at 0-5°C was dropwise added a solution of sodium nitrite (4.06 g, 58.8 mmol) in water (10 ml). Was stirred in an ice bath for 1 h, was added acetic acid (20 ml, 349 mmol), was heated with stirring at 80-85°C for 1 h, the solution was filtered hot to remove insoluble black material was cooled to 0-5°C, kept for 30 minutes, the precipitate was separated, washed with water, dried in vacuo at 45°C. the Yield of 9.48 g (90%).

A solution of 1H-benzo[d][1,2,3]triazole (0.5 g, 4.20 mmol) in tetrahydrofuran (25 ml) was added dropwise to a stirred 20% solution of phosgene (5.30 ml, 10.1 mmol) in toluene at 0-5°C. the Reaction mixture was stirred at 20-25°C for 2 h (completion of reaction was monitored by TLC). Within 15 minutes the solution was barbotirovany argon. Then the solvent was removed under vacuum and obtained 1H-benzo[d][1,2,3]triazole-1-carbonyl chloride(0.763 g, 4.20 mmol) as a clear oil. The product was used without further purification. Pyridine (0.357 ml, 4.41 mmol) was added to pocaply to a stirred solution of the oil in tetrahydrofuran (25 ml) at 0-5°C.
Then was added dropwise N-methylcyclohexylamine (0.499 g, 4.41 mmol) at 0-5°C. the Reaction mixture was stirred overnight at 20-25°C. was Added water and EtOAc and the separated organic layer was washed with 1M HCl, water and brine. The organic layer was dried (SO4) and was evaporated in vacuum to yield a light oil. The oil is recrystallized in 2-propanol/was held(dichloro methane), collecting solid residue was dried in vacuo at 40-45°C. Yield 230 mg (21%).

To a solution of 1H-benzo[d][1,2,3]triazole (0.238 g, 2 mmol) in dry was held (5 ml) was added at 0-5°C 20% solution of phosgene (1.052 ml, 2.000 mmol) in toluene. The mixture was stirred for 30 min at 20-25°C, cooled to 0-5°C with stirring was added triethylamine (0.279 ml, 2.000 mmol). Suspensio was diluted with dry was held (5 ml) was added solid (R)-Hinkley-3-amine dihydrochloride (0.398 g, 2.000 mmol) and triethylamine (0.836 ml, 6.00 mmol) at 0-5°C. the Mixture was allowed to heat up to 20-25°C for 30 min, diluted with 2-propanol was evaporated to dry residue. The residue was distributed between water (15 ml) and was held (15 ml), the organic phase was dried (MgSO4), concentrated, separated on a column (was held-MeOH 9:1), fractions were collected with getting oil. The oil was dissolved in ether with a�real number was held,
the solution was acidified using 2M HCl in ether to pH 1-2, the precipitate was collected, washed with ether, dried in vacuo at 45°C. the Yield of 0.12 g (19.5%).

(4-Isocyanurate)benzene (463 mg, 2.64 mmol) was added dropwise to a stirred solution of 1H-benzo[d][1,2,3]triazole (300 mg, 2.52 mmol) was held in (18 ml) at 0-5°C. a Transparent reaction mixture was stirred at 20-25°C during the night. The solvent was removed under vacuum to yield a light oil. Oil hardened when standing with the formation of a colorless solid substance. The product was crystallizable from 2-propanol, the solid is collected, dried in vacuo at 45°C. the Yield 477 mg (64%).

The IMIDAZOLOV:

4-(4-Fluorophenyl)-1H-imidazole (synthesis of imidazole)

In pear-shaped flask of 50 ml was placed 2-bromo-1-(4-fluorophenyl)alanon (5.93 g, 27.31 mmol), formamide (13.45 ml, 339 mmol) and water (1 ml). The reaction mixture was heated at 140°C for 4 hours. Then cooled to room temperature and poured into 150 ml of water. The precipitate was filtered, washed with water. the pH of the filtrate was adjusted to 12 by adding 10% NaOH solution. The resulting precipitate was filtered, washed with water and dried under vacuum. (Yield: 2.02 g, 45%).

To a cooled mixture of methanol - dry ice solution of N-(4-fluorophenyl)-4-(4-methoxyphenyl)-N-methyl-1H-imidazol-1-carboxamide (0.283 g, 0.870 mmol) in dichloromethane (8 ml) was added tribromide boron (0.164 ml, 1.740 mmol). The dark reaction mixture was warmed to room temperature and stirred for 2 hours. TLC showed completion of the reaction, the reaction mixture was poured into a mixture of ice and water and stirred 30 min. the Precipitate was not. The mixture was extracted with was held:IPA (70:30), the organic phase was dried over MgSO4and was filtered. Was held was removed under vacuum and the product was wizardly in the ISS, was filtered and dried under vacuum. (Yield: 210 mg, 78%)./p>

1,2,4-TRIAZOLES:

3-(4-Chlorophenyl)-1H-1,2,4-triazole (synthesis of ring)

4-Chlorobenzamide (7.371 g, 47.4 mmol) was suspended in 1,1-dimethoxy-N,N-dimethylethanamine (15.73 ml, 118 mmol). The reaction mixture was heated at 80°C for 1 hour. Then cooled to room temperature and the excess 1,1-dimethoxy-N,N-dimethylethanamine was removed under vacuum. The resulting solid substance was ground into powder with petroleum ether, filtered and dried under vacuum. (Yield: 9.44 g, 95%).

To a stirred solution of (E)-4-chloro-N-((dimethylamino)methylene) benzamide derivative (9.4 g, 44.6 mmol) in acetic acid (13.5 ml) was added hydrazine hydrate (1.524 ml, 49.1 mmol). The reaction mixture was hardened, and heated at 120°C for 2 hours. Then cooled to room temperature and azeotrope was distilled with toluene. The crystalline residue was stirred with water for some time. The precipitate was filtered, washed with water and dried under vacuum. (Yield: 7.27 g, 91%).

To a stirred solution of 3-(4-methoxyphenyl)-1H-1,2,4-triazole (701 mg, 4 mmol) in tetrahydrofuran (20 ml) was added pyridine (0.489 ml, 6.00 mmol), DMAP (48.9 mg, 0.400 mmol). The solution was treated with morpholino-4-carbonyl chloride (0.490 ml, 4.20 mmol) and heated at 90°C in tech�of 20 hours.
TLC showed almost full completion of the reaction. THF was removed under vacuum, the residue was distributed between and water was held. The organic phase was dried over MgSO4, was filtered and was evaporated. Recrystallization from hot IPA give 749 mg of white crystals. (Yield: 65%).

1,2,3-TRIAZOLES:

4-Phenyl-1H-1,2,3-triazole (synthesis of ring)

To a stirred solution of phenylacetylene (1.098 ml, 10 mmol) in absolute toluene (10 ml) was added one portion of azithromyycin (2.65 ml, 20.00 mmol). The reaction mixture was heated at 100°C for 3 days, then cooled to room temperature and toluene was removed under vacuum. The residue was distributed between and water was held. The organic phase was dried over MgSO4and was filtered. After evaporation the crude product was chromatographically a mixture of petroleum ether: EtOAc=2:1. (Yield: 355 mg, 24%).

Morpholino(4-phenyl-1H-1,2,3-triazole-1-yl)methanol (acylation)

To a stirred solution of 4-phenyl-1H-1,2,3-triazole (0.340 g, 2.342 mmol) in tetrahydrofuran (12 ml) was added pyridine (0.286 ml, 3.51 mmol), DMAP (0.029 g, 0.234 mmol). The solution was treated with a morpholine-4-carbonyl chloride (0.287 ml, 2.459 mmol). The reaction mixture was heated at 90°C for 20 hours. Then THF was removed under vacuum, the residue was distributed between and water was held. The organic phase was dried over MgSO4and was filtered. After pariani� recrystallized from IPA,
was filtered and dried under vacuum. (Yield: 193 mg, 29%).

The PYRAZOLES:

3-phenyl-1H-pyrazole (synthesis of ring)

Acetophenon (5.89 ml, 50 mmol) was dissolved in 1,1-dimethoxy-N,N-dimethylethanamine (13.39 ml, 100 mmol). The reaction mixture was heated at 120°C for 24 hours. Dark-red solution was cooled to room temperature and the excess 1,1-dimethoxy-N,N-dimethylethanamine was removed under vacuum. The resulting solid substance was ground into powder with petroleum ether, filtered and dried under vacuum. (Yield: 6.78 g, 77%).

To a stirred solution of (E)-3-(dimethylamino)-1-phenylprop-2-EN-1-one (2.63 g, 15 mmol) in ethanol (40 ml) was added hydrazine hydrate (1.459 ml, 30.0 mmol). The reaction mixture was heated at 100°C for 2 hours. Then cooled to room temperature and ethanol was distilled under vacuum. The residue was distributed between and water was held. The organic phase was dried over MgSO4and was filtered. After evaporation the crude product was purified by trituration with a mixture of petroleum ether and ethyl acetate. (Yield: 1.59 g, 73%).

Morpholino(3-(pyridin-3-yl)-1H-pyrazol-1-yl)methanon(acylation)

To a stirred solution of 3-(1H-pyrazol-3-yl)pyridine (0.435 g, 3 mmol) in tetrahydrofuran (15 ml) was added pyridine(0.367 ml, 4.50 mmol), DMAP (18.33 mg, 0.150 mmol). The solution was treated with 4-Mor�aminocarbonyl chloride (0.368 ml,
3.15 mmol). The reaction mixture was heated at 80°C for 20 hours. THF was removed under vacuum, the residue was distributed between and water was held. The organic phase was dried over MgSO4and was filtered. After evaporation the crude product was chromatographically a mixture of petroleum ether: EtOAc=2:1. (Yield: 174 mg, 21%).

BENZOIMIDAZOLE:

N-methyl-N-phenyl-1H-benzo[d]imidazole-1-carboxamide (acylation)

To a stirred solution of 1H-benzo[d]imidazole (354 mg, 3 mmol) in tetrahydrofuran (15 ml) was added pyridine (0.367 ml, 4.50 mmol) and then was added methyl(phenyl)carbamino chloride (534 mg, 3.15 mmol). The reaction mixture was heated at 80°C for 20 hours. THF was removed under vacuum, the residue was distributed between and water was held. The organic phase was dried over MgSO4and was filtered. After evaporation the crude product was chromatographically a mixture of petroleum ether: EtOAc=2:1. (Yield: 365 mg, 46%).

The following section provides additional examples of the synthesis of individual compounds.

The preparation of the compound 362

a) N-cyclohexyl-N-methyl-4-(pyridin-3-yl)-1H-imidazole-1-carboxamide

To a stirred suspension of 3-(1H-imidazol-4-yl)pyridine dihydrochloride (1.745 g, 8 mmol) in a mixture of tetrahydrofuran (29 ml) and DMF (2.90 ml) was added 2-methylpropan-2-Olathe potassium (1.795 g, 16.0 mmol) and the mixture was boiled to reflux for 30 minutes. Semi�enny brown suspension was cooled to room temperature and treated with pyridine (0.979 ml,
12 mmol) and N,N-dimethylpyridin-4-amine (0.098 g, 0.8 mmol) and then was added methyl(phenyl)carbamino chloride (1.476 g, 8.4 mmol). The reaction mixture was heated at 90°C overnight, after which the mixture was diluted with water and was extracted with ethyl acetate. The organic phase was dried (MgSO4) and was filtered. After evaporation the crude product was chromatographically on silica gel using a mixture of dichloro methane/methanol (9:1). Homogeneous fractions were combined and evaporated to give a white powder (160 mg, 7%).

To a stirred solution of N-cyclohexyl-N-methyl-4-(pyridin-3-yl)-1H-imidazol-1-carboxamide (90 mg, 0.317 mmol) in chloroform (5 ml) was added in one portion 3-chlormadinone acid (149 mg, 0.475 mmol). The reaction mixture was stirred at room temperature for 20 hours. TLC showed the completion of reaction, and the mixture was evaporated to dry residue. The residue was ground into powder with ether, and the resulting white crystals were filtered and air dried. Recrystallization from hot isopropanol gave a white powder (46 mg, 46%).

N-cyclohexyl-4-(3-hydroxyphenyl)-N-methyl-1H-imidazole-1-carboxamide (70 mg,
0.568 mmol) was placed in anhydrous tetrahydrofuran under nitrogen (10 ml) and the obtained colorless solution. Was added N-beta-hydroxyethylation (0.068 ml, 0.568 mmol) and the solution was cooled to 0°C. was Added triphenylphosphine (179 mg, 0.681 mmol), and then was dripped DEAD (0.108 ml, 0.68 mmol), and every next drop was added after the yellow discoloration that appeared after adding each drop. The obtained pale yellow solution was allowed to warm to room temperature and stirred 18 h. the Reaction mixture was cooled to 0°C and was added another portion of triphenylphosphine (179 mg, 0.681 mmol) and DEAD (0.108 ml, 0.68 mmol). The solution was stirred for another 6 hours. The solvent was evaporated and the yellow oil was purified by chromatography (silica gel H; 9/1, 8/2, 6/4, 5/5, 4/6 toluene/acetone). Fractions with pure product were evaporated and the pale yellow oil was dissolved in ethyl acetate, which then precipitate. The suspension was heated to dissolve the solids, and then the solution was cooled to 0°C. was added dropwise an excess of 2 N HCl solution in ether. The resulting mixture was stirred at 0°C for 10 minutes, left to heat to room temperature and stirred for another 15 minutes. The precipitate was filtered, washed with ether and dried. Recrystallization from ethyl acetate gave pale cream solid, (39 mg, 14%).

In pear-shaped flask of 50 ml was placed N-cyclohexyl-4-(4-hydroxyphenyl)-N-methyl-1H-imidazole-1-carboxamide (200 mg, 0.668 mmol) in tetrahydrofuran (10 ml) under nitrogen with obtaining a pale pink solution. Was added tert-butyl-4-(2-hydroxyethyl)piperazine-1-carboxylate (184 mg, 0.8 mmol) and the solution was cooled to 0°C. was Added trimethylphosphine (210 mg, 0.801 mmol), then was pinned DEAD (0.127 ml, 0.8 mmol), and every next drop was added after the yellow discoloration that appeared after adding each drop. The obtained pale yellow solution was allowed to warm to room temperature and stirred 24 h. the Solvent was evaporated and the pale yellow oil was purified by chromatography (silica gel H; 10%, 20%, 30%, 40%, 50%, 60% acetone/toluene). Fractions with pure product were evaporated and beige solid (167 mg) was used for next step without further purification.

In pear-shaped flask of 25 ml was placed tert-butyl 4-(2-(4-(1-(cyclohexyl(methyl)carbamoyl)-1H-imidazol-4-yl)phenoxy)ethyl)piperazine-1-carboxylate (167 mg, 0.326 mmol). Was added trifluoroacetic acid (3 ml, 38.9 mmol) to give a pale yellow solution which was stirred at room temperature�e 1 hour.
The solvent was evaporated and the remaining yellow oil was dissolved in ethyl acetate and cooled to 0°C. Then was added an excess of 2 N HCl solution in ether. The mixture was stirred at 0°C for 10 minutes, the temperature was raised to room temperature and stirred for another 15 minutes. The mixture was evaporated and the residue recrystallized from isopropanol. The crystals were filtered, washed with isopropanol and dried, was obtained the product as a white solid, (115 mg, 69%).

A solution of 1H-benzo[d][1,2,3]triazole-5-carboxylic acid (3 g, 18.39 mmol) in a mixture of tetrahydrofuran (90 ml) and dimethylformamide (50 ml) was added dropwise to a stirred suspension of sodium hydride (1.839 g, 46 mmol) in tetrahydrofuran (30 ml) at 0°C. the Suspension was stirred at room temperature for 30 minutes, then at 0°C was pinned a solution of 4,4-dimethoxyquinazoline-3-carbonyl chloride (3.16 g, 19.31 mmol) in tetrahydrofuran (10 ml). The reaction mixture was stirred at room temperature for 4 hours. Was added water at 0°C and the solvent was evaporated. Was added a mixture of dichloro methane/isopropanol (7:3) and separated the organic layer. The aqueous layer was re-extracted with dichloromethane, and the combined organic layers were dried (MgSO4), filter�and and was evaporated.
The orange residue was recrystallized from isopropanol to obtain a beige solid (840 mg), which was used for next step without further purification.

Thionyl chloride (0.633 ml, 8.67 mmol) was added dropwise to a stirred solution of 1-(4,4-dimethyloxazolidine-3-carbonyl)-1H-benzo[d][1,2,3]triazole-6-carboxylic acid (0.763 g, 2.63 mmol) and pyridine (0.702 ml, 8.67 mmol) in dichloromethane (17 ml) at room temperature. The yellow solution was stirred at room temperature for 15 minutes. This solution is then added dropwise to 1.75 N aqueous ammonia (15.02 ml, 26.3 mmol) in ethanol at 0°C, after which formed a white suspension. The reaction mixture was stirred at room temperature for another 30 minutes. Added water and methanol was evaporated. Then the residue was diluted with dichloromethane, the organic layer was separated and washed with 1 N HCl solution. The organic layer was dried (MgSO4), was filtered and was evaporated to obtain yellow solids. The solid is recrystallized from a mixture of dichloro methane/ethanol to give product in the form of a beige solid (151 mg, 20%).

A mixture of 4-(3-cyano-4-methoxyphenyl)-N-cyclohexyl-N-methyl-1H-imidazol-1-carboxamide (305 mg, 0.901 mmol), dibutylaniline (28.0 mg, 0.113 mmol) and azeotropically (0.239 ml, 1.803 mmol) was heated in toluene (8 ml) at 115°C for 20 h. Then the mixture was cooled to room temperature and was evaporated to dry residue. The crude product was chromatographically on silica using a mixture of dichloro methane/methanol (95:5). After evaporation of homogeneous fractions the residue was ground into powder with diethyl ether, filtered and dried to obtain a final product as an off-white crystals (196 mg, 54%).

A stirred mixture of 4-(3-(2-benzyl-2H-tetrazol-5-yl)phenyl)-N-cyclohexyl-N-methyl-1H-imidazol-1-carboxamide (256 mg, 0.58 mmol), 10% palladium on coal (30.9 mg, 0.029 mmol) and cyclohexene series (1.175 ml, 11.6 mmol) was heated at 80°C in a sealed tube. Then the reaction mixture was cooled to room temperature, filtered through celite and evaporated to dry residue. The resulting oil was purified by chromatography on silica using a mixture of dichloro methane/methanol (90:10). Homogeneous fractions were combined and evaporated and the remaining oil was crystallizable from diethyl ether to obtain a final product in the form of not �ovsem white powder,
(45 mg, 21%).

To a stirred suspension of 4-(3-(benzyloxycarbonyl)phenyl)-N-(1-benzylpiperidine-4-yl)-N-methyl-1H-imidazol-1-carboxamide (120 mg, 0.229 mmol) in dichloromethane (5 ml) at -78°C was added tribromsalan (0.022 ml, 0.229 mmol). The reaction mixture was stirred in the cold for 5 minutes and was raised to room temperature and stood for 1 hour. The mixture was cooled to -20°C and carefully poured onto methanol. Then the solvent was evaporated, and the residue obtained was transferred into a mixture of dichloro methane/isopropanol (7:3) and washed with saturated solution of NaHCO3then dried (MgSO4). After filtration, dichloro methane was evaporated to a small volume, and the resulting precipitate was filtered, washed with isopropanol and dried to obtain a final product in the form of not quite white powder (58 mg, 55%).

In a round bottom flask of 25 ml was placed 4-(4-cyanophenyl)-N-N-cyclohexyl-N-methyl-1H-imidazole-1-carboxamide (600 mg, 1.946 mmol) in ethanol (9 ml) at room temperature with obtaining white suspensie. Was added dropwise a 50% solution of hydroxylamine in�e (0.298 ml,
4.86 mmol) and the resulting mixture was heated at 90°C for 90 minutes. Then the mixture was cooled to room temperature, the precipitate was filtered and washed with ethanol. The solid is recrystallized from a mixture of hot ethyl acetate (~70 ml) and petroleum ether (~150 ml). The crystals were filtered off, washed with petroleum ether and dried to give a white solid, (230 mg, 29%).

In pear-shaped flask of 25 ml was placed (Z)-R-cyclohexyl-4-(4-(N'-hydroxycarbamoyl)phenyl)-N-methyl-1H-imidazole-1-carboxamide (228 mg, 0.668 mmol) in anhydrous dichloromethane (3 ml) under nitrogen to obtain a white suspension. Was added triethylamine (0.102 ml, 0.735 mmol), the suspension was cooled to 0°C and stirred for 30 minutes. Then was added dropwise methyl ester of Harborview acid (0.065 ml, 0.835 mmol) and the mixture was stirred at 0°C for 30 minutes, then the temperature was raised to room temperature and stirred for another 30 minutes. The precipitate was filtered and dissolved in a mixture of isopropanol and dichloromethane (3:7). This solution was combined with the previously obtained filtrate, and washed with 1 N HCl, water and brine, then dried (MgSO4), filtered and evaporated to give a white solid, (228 mg, 82%).

In pear-shaped flask of 50 ml was placed (Z)-N-cyclohexyl-4-(4-(N'-(methoxycarbonylamino)carbamimidoyl)phenyl)-N-methyl-1H-imidazole-1-carboxamide (200 mg, 0.501 mmol) in xylene (10 ml) under nitrogen to obtain a white suspension. The mixture was heated at 140°C for 4 hours and then cooled to room temperature. The precipitate was filtered, and the filter cake was washed with xylene. After drying, this solid substance was dissolved in a mixture of dichloromethane and isopropanol. After evaporation to a small volume, the solution was cooled to room temperature, the precipitate was filtered and dried to obtain the final product as a pale pink solid, (134 mg, 69%).

10% Palladium on coal (0.122 g, 0.115 mmol) was added to a stirred solution of N-cyclohexyl-N-methyl-4-(3-nitrophenyl)-1H-imidazol-1-carboxamide (0.755 g, 2.299 mmol) in a mixture of ethyl acetate (46 ml) and methanol (46 ml) in an argon atmosphere at room temperature. The mixture is then stirred at room temperature under a hydrogen atmosphere for 50 minutes. The mixture was filtered through celite, and the residue was washed with methanol. The combined filtrates were evaporated to obtain a pale oil/foam (691 mg, 100%), which is used to�litovali the next step without further purification.

Gaseous anhydrous hydrogen chloride (0.096 ml, 1.156 mmol) was added to a stirred suspension of 4-(3-Dapsone base)-N-cyclohexyl-N-methyl-1H-imidazol-1-carboxamide (0.345 g, 1.156 mmol) and cyanamide (0.135 ml, 1.734 mmol) in ethanol (1.2 ml) at room temperature. Light the solution was stirred while boiling to reflux for 1 hour and received a colorless solid. The reaction mixture was stirred while boiling with reflux for another 7 hours, then the mixture was cooled. The solid is separated by filtration and washed with ethanol to give product as colorless solids (298 mg, 68%).

Tetrakis(triphenylphosphine)palladium complex (0.076 g, 0.066 mmol) was added to a stirred dispersion of N-(1-benzylpiperidine-4-yl)-4-(3-bromophenyl)-N-methyl-1H-imidazol-1-carboxamide (0.600 g, 1.323 mmol), 3-carbamoilirovaniem acid (0.229 g, 1.390 mmol) and 2 M solution of sodium carbonate (0.794 ml, 1.588 mmol) in a mixture of 1-propanol (5 ml) and water (1 ml) at room temperature. The reaction mixture was stirred at 90°C for 1 hour. Water �delali,
and the organic layer was diluted with a mixture of dichloro methane/isopropanol (7:3). The organic layer was separated, dried (MgSO4), was filtered and was evaporated to obtain an orange oil. Column chromatography (silica, dichloro methane/methanol 5%) gave the product as an orange oil. The oil was triturated with a mixture of petroleum ether/ethyl acetate/ether, obtained the product as a beige solid (123 mg, 17%).

10% Palladium on charcoal (0.16 g, 0.15 mmol) was added to a stirred solution of N-cyclohexyl-4-(4-methoxy-3-nitrophenyl)-N-methyl-1H-imidazol-1-carboxamide (1.075 g, 3 mmol) in a mixture of ethyl acetate (50 ml) and methanol (50 ml) at room temperature in an argon atmosphere. Hydrogen was barbotirovany through the solution for 1 hour. The solution was filtered through celite, and the residue was washed with ethyl acetate. The combined filtrates were evaporated to obtain a brown masaabeeh solid which was used in next step without further purification.

Mesyl chloride (0.247 ml, 3.17 mmol) was added to a stirred solution of 4-(3-amino-4-methoxyphenyl)-N-cyclohexyl-N-methyl�-1H-imidazol-1-carboxamide (1.04 g,
3.17 mmol) and triethylamine (0.441 ml, 3.17 mmol) in tetrahydrofuran (6 ml) at room temperature. The brown mixture was stirred at room temperature for weeks. The water was separated and the solvent was evaporated. Then the aqueous layer was acidified using, and the residue was extracted with ethyl acetate. The aqueous layer was twice extracted with a mixture of dichloro methane/isopropanol (7:3). The organic layer was separated, dried (MgSO4), filtered and evaporated, receiving not quite white solid. The solid is recrystallized from a mixture of ethanol/dichloro methane, not quite white solid (434 mg, 34%).

The sulphonamide (0.089 g, 0.922 mmol) was added to a stirred suspension of 4-(4-Dapsone base)-N-cyclohexyl-N-methyl-1H-imidazol-1-carboxamide (0.250 g, 0.838 mmol) in dioxane (2 ml) at room temperature. The suspension was boiled to reflux for 4 hours with light mortar, then added the sulphonamide (0.089 g, 0.922 mmol) and the mixture was boiled to reflux for 2.5 h. the Solvent was removed and the brown residue was purified by chromatography (silica, dichloro methane/methanol, 1%, 2%, 5%). Homogeneous fractions were combined and evaporated. The residue was triturated with ethyl acetate, and the resulting colorless solid was separated by filtration. The filtrate was concentrated and purified using preparative TLC (silica, dichloro methane/10% methanol). The product was extracted from silica with a mixture of ethyl acetate/10% methanol. After evaporation of solvent received light oil, which was triturated with a mixture of ethyl acetate and methanol, received the product as an off-white solid (19 mg, 6 %).

Triethylamine (.159 ml
1.139 mmol) was added to a stirred suspension of 4-(3-fluoro-4-methoxyphenyl)-N-methyl-N-(piperidine-4-yl)-1H-imidazole-1-carboxamide hydrochloride (0.200 g, 0.542 mmol) and 3-chloropropionitrile (0.058 g, 0.651 mmol) at room temperature. Bright solution under stirring heated to reflux for 2 h, during this time formed a white suspension. The mixture was cooled to room temperature, mixture was diluted with dichloro methane/isopropanol (7:3) and then washed with water. The organic layer was dried (MgSO4), filtered and evaporated, receiving not quite white solid, which was triturated with ethanol, got the final product (142 mg, 64%).

In a round bottom flask of 100 ml was placed 1H-benzo[d][1,2,3]triazole-5-carboxylic acid (510 mg, 3.126 mmol) in anhydrous tetrahydrofuran (10 ml) under nitrogen, was obtained a brown sospesi. Added portions of the DNS (558 mg, 3.439 mmol) and the mixture stirred at room temperature for 1.5 h. Then was added in portions 1-cyclohexylpiperazine (658 mg, 3.908 mmol) and the resulting brown solution was stirred at room temperature for 30 minutes. The solvent was evaporated and the brown oil was treated with a mixture of 30% isopropanol/dichloro methane/water. Section�Yali phase,
the organic phase was washed with water and brine, then dried (MgSO4), was filtered and was evaporated. The obtained beige foam was purified by chromatography (silica gel; dichloro methane, 2%, 3%, 5% methanol/dichloro methane). Fractions with pure product were evaporated and light orange foam was triturated with heptane. The solid was filtered and dried, received a beige solid, (605 mg, 54%).

In a round bottom flask of 100 ml was placed (1H-benzo[d][1,2,3]triazole-5-yl)(4-cyclohexylpiperazine-1-yl)methanon (612 mg, 1.953 mmol) in tetrahydrofuran (15 ml) and N,N-dimethylformamide (3 ml), received a pale yellow solution. This solution was cooled to 0°C was added a 60% dispersion of sodium hydride in mineral oil (70.3 mg, 2.93 mmol). The obtained pale-pink solution was heated to room temperature and stirred for 45 minutes. The mixture is then again cooled to 0°C and dropwise added a solution of 4,4-dimethyloxazolidine-3-carbonyl chloride (351 mg, 2.148 mmol) in tetrahydrofuran (2.5 ml). The obtained pale yellow solution was warmed to room temperature and stirred for 4 hours. The solvent was evaporated, to the residue was added water and was extracted with toluene. The organic phase was washed with water and brine, then sushi�Lee (MgSO
4), was filtered and was evaporated. The obtained yellow oil was purified by chromatography (silica gel; dichloro methane, 2% methanol/dichloro methane). Fractions with pure product were combined and evaporated, received a pale yellow foam (690 mg, 80%).

In pear-shaped flask of 50 ml was placed (4-cyclohexylpiperazine-1-yl)(2-(4,4-(4,4-dimethyloxazolidine-3-carbonyl)-2H-benzo[d][1,2,3]triazole-5-yl)methanon (300 mg, 0.681 mmol) in methanol (5 ml) at room temperature, received a yellow solution. Was added one portion of the dihydrate of oxalic acid (86 mg, 0.681 mmol) and the solution was stirred at room temperature for 2 hours. The solvent was evaporated and the obtained pale-yellow foam was crystallizable from isopropanol. After filtration and drying received the product as a white solid, (150 mg, 39%).

To a solution of 4-(4-methoxyphenyl)-N-methyl-N-(piperidine-4-yl)-1H-imidazole-1-carboxamide hydrochloride (287 mg, 0.818 mmol) in DMF (5 ml) was added tert-butoxide potassium (184 mg, 1.636 mmol) and the mixture was stirred at room temperature for 30 minutes, then cooled in a bath of ice/water and was added dropwise to brazian (0.818 ml, 2.454 mmol, 3 N dichlormethane solution) for 10-15 minutes. The reaction mixture was slowly warmed to room temperature in tech�of 1 hour,
then added water and dichloro methane/isopropanol (7:3). The layers were separated and the organic phase was washed with water and brine, then dried (Na2SO4), filtered and removed rhetorical when panigram pressure. The residue was dissolved in a minimum volume of chloroform, and insoluble material was removed by filtration. The filtrate was concentrated and got a not quite white solid, (345 mg, 67%).

To a suspension of N-(1-cyanopiperidine-4-yl)-4-(4-methoxyphenyl)-N-methyl-1H-imidazol-1-carboxamide (151 mg, 0.445 mmol) in toluene (10 ml) was added dibutylamine (13.84 mg, 0.056 mmol), then azithromyycin (0.207 ml, 1.557 mmol). The reaction mixture was boiled to reflux for 5 hours, then filtered still hot and received pink the solid is then washed with toluene, dichloromethane and finally with ether. The solid was precrystallization from methanol, received the product as a light pink solid, (100 mg, 56%).

2. Examples of connections

No.

Structure

3

1

4

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5

6

11

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597

The above soedineniya according to the invention were characterized using the melting point and NMR, as described in detail below. NMR spectra were recorded on a Bruker Avance DPX400 with the solvent used as internal standard. 13 C spectra were recorded at 100 MHz and 1H spectra were recorded at 400 MHz. Data is recorded as follows: the relative chemical shift (M. D.), the number of protons, the multiplicity of the signals (W, broad; d, doublet; m, multiplet; s, singlet; t, triplet) and the interaction constant (Hz).

Tests in vitro were performed in accordance with the Protocol described below. Control for in vitro and in vivo have been the reaction mixture minus the tested compounds. Therefore, a low value in Table 1 for the tested compounds shows a strong inhibitor. A value of 100 indicates that there is no measurable inhibition.

Tests in vivo were performed in accordance with the Protocol described below. BRh shows inhibition in the tissues of the Central nervous system, a LVh shows inhibition in peripheral tissues, in this case, in the liver.

In vitro Protocol

Pharmaceutical FAAH activity in vitro was determined in the following way:

Used frozen brains (without cerebellum) laboratory of Wistar rats, each brain was homogenized in 15 ml of 1 mm MgCl2, 20 nm HEPES pH 7.0 using a Potter Elvejhem (8 strokes at 500 rpm). The homogenates were centrifuged for 20 min at 36000g at 4°C (Beckman, 70Ti rotor). Pellets were resuspended in 15 ml of the same buffer and centrifuged under the same conditions. Pellets were resuspended in 15 ml of the same buffer and incubated for 15 minutes at 37°C,
then centrifuged for 20 min at 36000g at 4°C. Each pellet then was resuspended in 15 ml of 3 mm MgCl2, 1 mm EDTA, 50 mm Tris pH 7.4 and protein was determined using the BioRad Protein Assay (BioRad) using BSA standard curve (50-250 µg/ml). Membrane suspensie were divided into aliquots and stored at -80°C.

FAAH activity was determined using AEA (labeled by 3H in ethanolamine part of the molecule) as substrate and measuring the formation of 3H-ethanolamine. The reaction mixture (total volume 200 µl) contained: 2 μm AEA (2 μm AEA + 5 nm 3H-AEA), 0.1% free fatty acid BSA (bovine serum albumin), 5 µg of protein in 1 mm EDTA (ethylenediaminetetraacetic acid), 10 mm Tris pH 7.6 and 10 μm or 0.1 μm of the compounds. Stock solutions of compounds for testing (10 mm) was prepared in 100% DMSO, and the concentration of DMSO in the sample was 0.1%. After 15 min pre-incubation at 37°C, the reaction started by adding the substrate solution (cold EAE + isotope-labeled EAE + BSA). The reaction was performed for 10 min, was completed by the addition of 400 μl of a suspension of activated charcoal (8 g of coal in 32 ml of 0.5 M HCl with constant stirring). After incubation for 30 min at room temperature with stirring, the charcoal was precipitated by centrifugation in a microcentrifuge (10 min at 13000 rpm). 200 μl of the supernatant was added to 80 µl of Optiphase Supermix scintillation mixture,
previously placed in 24-well plates. The number of counts per minute (cpm) was determined using a Microbeta TriLux scintillation counter (10 min account or until such time as s=2).

In each analysis were present in the blank samples (without protein, typically below 200 cpm) and control (without connections). The results are shown in Table 1, in the form of % control of the substrate relative to the source.

In vivo Protocol

Treatment of animals

As animals were used in the experiment male NMRI mice (weight 27-44 g), obtained from Interfauna Ibérica (Spain). Mice were kept at 5 in the cage, under controlled environmental conditions (12 h cycle of light/dark and room temperature 22±1°C). Food and tap water were allowed ad liutum (fluent) and all experiments were performed in the daytime.

Animals received 30 mg/kg or 3 mg/kg of the compounds according to the invention by the oral route (8 ml/kg; the compound was suspended in 0.5% carboxymethylcellulose (CMC) dissolved in water) or made (control), using curved stainless steel needles for animal feed (Perfectum, U. S. A.). 15 minutes before killing the animals were anesthetized by intraperitoneal injection of 60 mg/kg of pentobarbital. Selected fragment of the liver, the left lobe of the lung and brain without cerebellum and placed in plastic tubes containing membrane buffer (3 mm MgCl2, 1 mm EDTA, 50 mm Tris HCl pH 7.4). Fabric x�anili at -30°C until analysis.

The animals are fasted overnight prior to administration of the compounds, except for the time >18 h, when food was removed in the morning on the day of administration and the compound was administered in the afternoon of the same day. Animals then were given water, but nothing more.

All procedures with animals were performed in strict accordance with the European Directive for the protection of vertebrate animals used for experimental and other scientific purposes (86/EE) and Portuguese legislation (Decreto-Lei 129/92, Portarias 1005/92 e 1131/97). Used the minimum possible number of animals in compliance with current regulation and scientific purity.

Reagents and solutions

Anandamide [ethanolamine-1-3H-] (40-60Ci/mmol) was obtained in the firm American Radiochemicals. All other reagents obtained from the company Sigma-Aldrich. Optiphase Supermix was obtained in the firm Perkin Elmer, and activated carbon was obtained in the firm Sigma-Aldrich.